SHLD1

Summary

SHLD1 (shieldin complex subunit 1, HGNC:26318) is a protein-coding gene on chromosome 20p12.3, encoding Shieldin complex subunit 1 (Q8IYI0). Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs). It is a selective cancer dependency (DepMap: 10.0% of cell lines).

Involved in negative regulation of double-strand break repair via homologous recombination; positive regulation of double-strand break repair via nonhomologous end joining; and positive regulation of isotype switching. Located in site of double-strand break.

Source: NCBI Gene 149840 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 5 total
• Cancer dependency (DepMap): dependent in 10.0% of screened cell lines
• MANE Select transcript: NM_152504

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26318
Approved symbol	SHLD1
Name	shieldin complex subunit 1
Location	20p12.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25067, RINN3
Ensembl gene	ENSG00000171984
Ensembl biotype	protein_coding
OMIM	618028
Entrez	149840

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000303142, ENST00000378979, ENST00000442185, ENST00000445603, ENST00000875759, ENST00000915775, ENST00000915776, ENST00000962423, ENST00000962424

RefSeq mRNA: 4 — MANE Select: NM_152504 NM_001303477, NM_001303478, NM_001303479, NM_152504

CCDS: CCDS13091, CCDS77565

Canonical transcript exons

ENST00000303142 — 3 exons

Exon	Start	End
ENSE00001225182	5863024	5864395
ENSE00001881811	5750401	5750479
ENSE00003617198	5772862	5773043

Expression profiles

Bgee: expression breadth ubiquitous, 190 present calls, max score 88.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.7598 / max 147.2500, expressed in 1637 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183351	5.4114	1605
183352	0.3484	158

Top tissues by expression

246 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.86	gold quality
monocyte	CL:0000576	84.73	gold quality
leukocyte	CL:0000738	84.28	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.15	gold quality
oocyte	CL:0000023	82.41	gold quality
pancreatic ductal cell	CL:0002079	81.20	silver quality
gastrocnemius	UBERON:0001388	81.01	gold quality
muscle of leg	UBERON:0001383	80.07	gold quality
right adrenal gland	UBERON:0001233	79.59	gold quality
left adrenal gland cortex	UBERON:0035825	79.27	gold quality
left adrenal gland	UBERON:0001234	79.26	gold quality
right adrenal gland cortex	UBERON:0035827	79.22	gold quality
blood	UBERON:0000178	78.94	gold quality
lymph node	UBERON:0000029	78.90	gold quality
right atrium auricular region	UBERON:0006631	78.41	gold quality
adrenal gland	UBERON:0002369	78.19	gold quality
adrenal cortex	UBERON:0001235	77.98	gold quality
hindlimb stylopod muscle	UBERON:0004252	77.85	gold quality
adrenal tissue	UBERON:0018303	77.81	gold quality
spleen	UBERON:0002106	77.45	gold quality
mucosa of transverse colon	UBERON:0004991	77.43	gold quality
islet of Langerhans	UBERON:0000006	77.40	gold quality
cardiac atrium	UBERON:0002081	77.40	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	77.38	gold quality
ventricular zone	UBERON:0003053	76.37	gold quality
granulocyte	CL:0000094	76.31	gold quality
ganglionic eminence	UBERON:0004023	76.30	gold quality
cortical plate	UBERON:0005343	76.30	gold quality
buccal mucosa cell	CL:0002336	76.23	gold quality
vermiform appendix	UBERON:0001154	76.21	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

41 targeting SHLD1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-3689A-5P	98.35	70.12	1049
HSA-MIR-3689B-5P	98.35	70.12	1049
HSA-MIR-3689E	98.35	70.12	1049
HSA-MIR-3689F	98.35	70.08	1052
HSA-MIR-541-5P	98.24	67.77	1181
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-876-5P	97.99	68.49	1345
HSA-MIR-3159	97.94	66.79	1098

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 2)

• Protein phosphatase 1 acts as a RIF1 effector to suppress DSB resection prior to Shieldin action. (PMID:34260925)
• MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair. (PMID:34521823)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Shld1	ENSMUSG00000044991
rattus_norvegicus	Shld1	ENSRNOG00000021268

Protein

Protein identifiers

Shieldin complex subunit 1 — Q8IYI0 (reviewed: Q8IYI0)

Alternative names: RINN1-REV7-interacting novel NHEJ regulator 3, Shield complex subunit 1

All UniProt accessions (4): Q8IYI0, A0A0A0MSQ5, Q5TGA6, Q5TGB0

UniProt curated annotations — full annotation on UniProt →

Function. Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs). During G1 and S phase of the cell cycle, the complex functions downstream of TP53BP1 to promote non-homologous end joining (NHEJ) and suppress DNA end resection. Mediates various NHEJ-dependent processes including immunoglobulin class-switch recombination, and fusion of unprotected telomeres.

Subunit / interactions. Component of the shieldin complex, consisting of SHLD1, SHLD2, SHLD3 and MAD2L2/REV7. Within the complex, SHLD2 forms a scaffold which interacts with a SHLD3-MAD2L2 subcomplex via its N-terminus, and with SHLD1 via its C-terminus. Interacts with ASTE1.

Subcellular location. Chromosome.

Miscellaneous. In BRCA1-deficient cells, function of the shieldin complex is necessary for sensitivity to the PARP inhibitor olaparib.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IYI0-1	1	yes
Q8IYI0-2	2

RefSeq proteins (4): NP_001290406, NP_001290407, NP_001290408, NP_689717* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR027821	SHLD1	Family
IPR053898	SHLD1_C	Domain

Pfam: PF15021

UniProt features (3 total): chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IYI0-F1	66.93	0.17

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 159 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_B_CELL_ACTIVATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_DNA_REPAIR, GOBP_NEGATIVE_REGULATION_OF_DNA_RECOMBINATION, GOBP_TELOMERE_ORGANIZATION, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR_VIA_HOMOLOGOUS_RECOMBINATION, GOBP_POSITIVE_REGULATION_OF_B_CELL_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY

GO Biological Process (8): somatic diversification of immunoglobulins involved in immune response (GO:0002208), DNA repair (GO:0006281), telomere maintenance in response to DNA damage (GO:0043247), positive regulation of isotype switching (GO:0045830), negative regulation of double-strand break repair via homologous recombination (GO:2000042), positive regulation of double-strand break repair via nonhomologous end joining (GO:2001034), DNA damage response (GO:0006974), regulation of double-strand break repair via nonhomologous end joining (GO:2001032)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), chromosome (GO:0005694), site of double-strand break (GO:0035861)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA damage response	2
double-strand break repair via nonhomologous end joining	2
immunoglobulin production involved in immunoglobulin-mediated immune response	1
somatic diversification of immunoglobulins	1
DNA metabolic process	1
telomere maintenance	1
positive regulation of immunoglobulin production	1
positive regulation of immunoglobulin mediated immune response	1
isotype switching	1
regulation of isotype switching	1
positive regulation of DNA recombination	1
positive regulation of B cell activation	1
positive regulation of developmental process	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
negative regulation of DNA recombination	1
negative regulation of double-strand break repair	1
positive regulation of double-strand break repair	1
regulation of double-strand break repair via nonhomologous end joining	1
cellular response to stress	1
regulation of double-strand break repair	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membraneless organelle	1
site of DNA damage	1

Protein interactions and networks

STRING

458 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHLD1	SHLD2	Q86V20	998
SHLD1	MAD2L2	Q9UI95	996
SHLD1	SHLD3	Q6ZNX1	994
SHLD1	TP53BP1	Q12888	755
SHLD1	REV3L	O60673	640
SHLD1	FKBP1A	P20071	590
SHLD1	CTC1	Q2NKJ3	580
SHLD1	PAXIP1	Q6ZW49	570
SHLD1	TATDN3	Q17R31	518
SHLD1	RIF1	Q5UIP0	514
SHLD1	TRIP13	Q15645	509
SHLD1	RBBP8	Q99708	507
SHLD1	BRCA1	P38398	488
SHLD1	BEND7	Q8N7W2	478
SHLD1	RAD51	Q06609	473

IntAct

38 interactions, top by confidence:

A	B	Type	Score
QARS1	SHLD1	psi-mi:“MI:0915”(physical association)	0.560
SHLD1	APBB2	psi-mi:“MI:0915”(physical association)	0.560
SHLD1	DMWD	psi-mi:“MI:0915”(physical association)	0.560
SHLD1		psi-mi:“MI:0915”(physical association)	0.560
SHLD1	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
SHLD1	PMP22	psi-mi:“MI:0915”(physical association)	0.560
SHLD1	WFS1	psi-mi:“MI:0915”(physical association)	0.560
SHLD1	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
SHLD1	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
HTT	SHLD1	psi-mi:“MI:0915”(physical association)	0.560
SHLD2	SHLD1	psi-mi:“MI:0915”(physical association)	0.500
Mad2l2	CALU	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (26): MAD2L2 (Affinity Capture-Western), C20orf196 (Affinity Capture-Western), C20orf196 (Co-localization), FAM35A (Co-localization), MAD2L2 (Co-localization), C20orf196 (Co-localization), FAM35A (Affinity Capture-MS), GTF2F2 (Affinity Capture-MS), C20orf196 (Affinity Capture-MS), C20orf196 (Affinity Capture-MS), TP53BP1 (Co-localization), RIF1 (Co-localization), C20orf196 (Affinity Capture-Western), C20orf196 (Affinity Capture-MS), MAD2L2 (Affinity Capture-Western)

ESM2 similar proteins: A0A0F6B506, A8MTZ7, A8Y5T1, C9K7C3, F5H9W9, G1XTZ6, G4NB33, I1S490, K3VDP7, O09102, O92605, P03238, P09265, P09281, P0C6G3, P0C774, P0CK37, P0CK38, P13780, P14968, P14976, P17926, P21740, P21944, P26036, P27262, P28953, P28989, P36280, P46983, P53963, P53976, P70255, Q04329, Q06658, Q08588, Q08589, Q12379, Q4JQW5, Q6W0C5

Diamond homologs: Q2KIJ1, Q8IYI0, Q9D112

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

5 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	2
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1496 predictions. Top by Δscore:

Variant	Effect	Δscore
20:5772856:T:G	acceptor_gain	1.0000
20:5772856:T:TA	acceptor_gain	1.0000
20:5772859:CA:C	acceptor_loss	1.0000
20:5772860:A:AC	acceptor_loss	1.0000
20:5772860:AG:A	acceptor_gain	1.0000
20:5772861:GG:G	acceptor_gain	1.0000
20:5772861:GGA:G	acceptor_gain	1.0000
20:5772861:GGAC:G	acceptor_gain	1.0000
20:5772861:GGACT:G	acceptor_gain	1.0000
20:5772989:GCTT:G	donor_gain	1.0000
20:5750477:GAG:G	donor_gain	0.9900
20:5750480:G:A	donor_loss	0.9900
20:5750481:T:A	donor_loss	0.9900
20:5772855:A:AG	acceptor_gain	0.9900
20:5772855:AT:A	acceptor_gain	0.9900
20:5772855:ATG:A	acceptor_gain	0.9900
20:5772857:G:A	acceptor_gain	0.9900
20:5772860:A:AG	acceptor_gain	0.9900
20:5772861:G:GT	acceptor_gain	0.9900
20:5773039:TCCAG:T	donor_loss	0.9900
20:5773040:CCAGG:C	donor_loss	0.9900
20:5773041:CAGGT:C	donor_loss	0.9900
20:5773042:AG:A	donor_loss	0.9900
20:5773043:GGT:G	donor_loss	0.9900
20:5773044:G:GA	donor_loss	0.9900
20:5773045:T:C	donor_loss	0.9900
20:5773252:G:GT	donor_gain	0.9900
20:5831168:TTA:T	donor_gain	0.9900
20:5773004:G:GT	donor_gain	0.9800
20:5802141:G:GT	donor_gain	0.9800

AlphaMissense

1359 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:5863149:T:C	F102L	0.978
20:5863151:C:A	F102L	0.978
20:5863151:C:G	F102L	0.978
20:5863287:G:C	A148P	0.968
20:5863150:T:C	F102S	0.960
20:5863279:T:C	F145S	0.957
20:5863219:T:A	L125Q	0.950
20:5863288:C:A	A148D	0.950
20:5863219:T:C	L125P	0.943
20:5863428:T:C	F195L	0.939
20:5863430:C:A	F195L	0.939
20:5863430:C:G	F195L	0.939
20:5863408:T:C	L188P	0.938
20:5863273:G:C	R143P	0.933
20:5863350:T:C	F169L	0.930
20:5863352:C:A	F169L	0.930
20:5863352:C:G	F169L	0.930
20:5863263:T:C	Y140H	0.928
20:5863219:T:G	L125R	0.926
20:5863240:T:C	L132P	0.926
20:5863141:T:C	L99P	0.924
20:5863429:T:C	F195S	0.921
20:5863291:G:C	R149P	0.918
20:5863282:A:C	Q146P	0.915
20:5863432:T:C	L196P	0.914
20:5863264:A:C	Y140S	0.910
20:5863432:T:G	L196R	0.909
20:5863207:T:A	V121D	0.908
20:5863405:G:A	G187E	0.908
20:5863300:T:C	F152S	0.906

dbSNP variants (sampled 300 via entrez): RS1000097424 (20:5770459 G>C), RS1000103510 (20:5790580 G>A), RS1000111541 (20:5850122 A>G,T), RS1000116001 (20:5797090 A>G), RS1000128513 (20:5749928 A>G), RS1000148345 (20:5852448 C>G), RS1000150047 (20:5764348 A>G), RS1000165327 (20:5850422 G>A), RS1000172365 (20:5752317 A>T), RS1000184965 (20:5768057 C>T), RS1000216247 (20:5768251 G>A), RS1000315117 (20:5794017 C>T), RS1000328685 (20:5796319 A>G), RS1000347707 (20:5757133 C>G), RS1000486059 (20:5831038 T>C)

Disease associations

OMIM: gene MIM:618028 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST000905_6	Information processing speed	8.000000e-06
GCST006979_689	Heel bone mineral density	4.000000e-09
GCST007317_8	Response to ketamine in bipolar disorder or major depression (dissociation effects)	6.000000e-06
GCST012228_435	Waist-hip index	9.000000e-10
GCST012228_436	Waist-hip index	1.000000e-12
GCST012229_161	Hip index	4.000000e-08
GCST012230_175	Waist-to-hip ratio adjusted for BMI	1.000000e-09
GCST012230_176	Waist-to-hip ratio adjusted for BMI	2.000000e-12
GCST90020024_567	A body shape index	6.000000e-10
GCST90020025_1653	Waist-to-hip ratio adjusted for BMI	5.000000e-08
GCST90020025_1654	Waist-to-hip ratio adjusted for BMI	5.000000e-20
GCST90020025_1655	Waist-to-hip ratio adjusted for BMI	2.000000e-12
GCST90020026_96	Hip index	6.000000e-12
GCST90020027_324	Waist-hip index	4.000000e-08
GCST90020027_325	Waist-hip index	4.000000e-20
GCST90020027_326	Waist-hip index	1.000000e-12
GCST90020028_1336	Hip circumference adjusted for BMI	5.000000e-09
GCST90020029_177	Waist circumference adjusted for body mass index	5.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004363	information processing speed
EFO:0009270	heel bone mineral density
EFO:0009748	response to ketamine
EFO:0009750	dissociation measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, affects cotreatment	5
Benzo(a)pyrene	decreases expression, increases methylation	3
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Calcitriol	increases expression	1
Estradiol	decreases expression	1
Hydrogen Peroxide	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Silicon Dioxide	decreases expression	1
Thiram	increases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.