SHLD3

Summary

SHLD3 (shieldin complex subunit 3, HGNC:53826) is a protein-coding gene on chromosome 5q12.3, encoding Shieldin complex subunit 3 (Q6ZNX1). 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: 11.4% 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 nucleolus; nucleoplasm; and site of double-strand break.

Source: NCBI Gene 112441434 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 3 total
• Cancer dependency (DepMap): dependent in 11.4% of screened cell lines
• MANE Select transcript: NM_001365341

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:53826
Approved symbol	SHLD3
Name	shieldin complex subunit 3
Location	5q12.3
Locus type	gene with protein product
Status	Approved
Aliases	AC008560.1, FLJ26957, CTC-534A2.2, RINN1
Ensembl gene	ENSG00000253251
Ensembl biotype	protein_coding
OMIM	618030
Entrez	112441434

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000510585, ENST00000514404, ENST00000931102

RefSeq mRNA: 1 — MANE Select: NM_001365341 NM_001365341

CCDS: CCDS93722

Canonical transcript exons

ENST00000510585 — 2 exons

Exon	Start	End
ENSE00002041841	65625027	65625106
ENSE00002057630	65629468	65630928

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 81.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.9337 / max 215.3042, expressed in 1721 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56693	9.9337	1721

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	81.19	gold quality
leukocyte	CL:0000738	80.76	gold quality
cortical plate	UBERON:0005343	79.10	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.03	gold quality
islet of Langerhans	UBERON:0000006	76.84	gold quality
ganglionic eminence	UBERON:0004023	73.68	gold quality
granulocyte	CL:0000094	73.44	gold quality
calcaneal tendon	UBERON:0003701	73.02	gold quality
adrenal tissue	UBERON:0018303	72.76	gold quality
mucosa of transverse colon	UBERON:0004991	72.67	gold quality
rectum	UBERON:0001052	71.53	gold quality
ventricular zone	UBERON:0003053	71.15	gold quality
pancreas	UBERON:0001264	71.01	gold quality
right adrenal gland cortex	UBERON:0035827	70.93	gold quality
lymph node	UBERON:0000029	70.92	gold quality
adenohypophysis	UBERON:0002196	70.80	gold quality
bone marrow	UBERON:0002371	70.21	gold quality
gastrocnemius	UBERON:0001388	70.20	gold quality
left adrenal gland cortex	UBERON:0035825	70.18	gold quality
vermiform appendix	UBERON:0001154	70.09	gold quality
left adrenal gland	UBERON:0001234	69.97	gold quality
muscle of leg	UBERON:0001383	69.92	gold quality
right adrenal gland	UBERON:0001233	69.85	gold quality
hindlimb stylopod muscle	UBERON:0004252	69.67	gold quality
right lobe of liver	UBERON:0001114	69.62	gold quality
body of pancreas	UBERON:0001150	69.59	gold quality
small intestine Peyer’s patch	UBERON:0003454	69.55	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	69.29	gold quality
smooth muscle tissue	UBERON:0001135	69.09	gold quality
spleen	UBERON:0002106	69.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.57

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 11.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 1)

• Structural basis for shieldin complex subunit 3-mediated recruitment of the checkpoint protein REV7 during DNA double-strand break repair. (PMID:31796627)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:101664	ENSDARG00000035700
mus_musculus	Shld3	ENSMUSG00000118537
rattus_norvegicus	Shld3	ENSRNOG00000072257

Protein

Protein identifiers

Shieldin complex subunit 3 — Q6ZNX1 (reviewed: Q6ZNX1)

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

All UniProt accessions (1): Q6ZNX1

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.

RefSeq proteins (1): NP_001352270* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR039996	Shieldin_RINN1	Family

UniProt features (10 total): strand 3, region of interest 2, helix 2, chain 1, compositionally biased region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
6M7B	X-RAY DIFFRACTION	1.77
6M7A	X-RAY DIFFRACTION	1.9
6VE5	X-RAY DIFFRACTION	2
6K07	X-RAY DIFFRACTION	2.24
6K08	X-RAY DIFFRACTION	2.31
6WW9	X-RAY DIFFRACTION	2.7
6KTO	X-RAY DIFFRACTION	3.45
7L9P	ELECTRON MICROSCOPY	3.6
6WWA	X-RAY DIFFRACTION	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZNX1-F1	78.73	0.46

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (1):

Position	Phenotype
53–58	fails to interact with mad2l2.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 99 (showing top): 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, GOBP_B_CELL_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 homologous recombination (GO:0010569)

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

GO Cellular Component (5): chromatin (GO:0000785), nucleoplasm (GO:0005654), chromosome (GO:0005694), nucleolus (GO:0005730), 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 homologous recombination	2
cellular anatomical structure	2
nuclear lumen	2
intracellular membraneless organelle	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
regulation of double-strand break repair via homologous recombination	1
negative regulation of DNA recombination	1
negative regulation of double-strand break repair	1
double-strand break repair via nonhomologous end joining	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 DNA recombination	1
regulation of double-strand break repair	1
binding	1
chromosome	1
site of DNA damage	1

Protein interactions and networks

STRING

126 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHLD3	SHLD2	Q86V20	995
SHLD3	SHLD1	Q8IYI0	994
SHLD3	MAD2L2	Q9UI95	981
SHLD3	C20orf96	Q9NUD7	648
SHLD3	KIZ	Q2M2Z5	558
SHLD3	RIF1	Q5UIP0	519
SHLD3	TP53BP1	Q12888	506
SHLD3	USP28	Q96RU2	476
SHLD3	PAXIP1	Q6ZW49	474
SHLD3	TEN1	Q86WV5	455
SHLD3	TRAPPC13	A5PLN9	434
SHLD3	CTC1	Q2NKJ3	393
SHLD3	BRCA1	P38398	345
SHLD3	RBBP8	Q99708	341
SHLD3	RBMY1D	P0C7P1	300

IntAct

14 interactions, top by confidence:

A	B	Type	Score
SHLD3	MAD2L2	psi-mi:“MI:0915”(physical association)	0.650
SHLD3	MAD2L2	psi-mi:“MI:0407”(direct interaction)	0.650
SHLD3	MAD2L2	psi-mi:“MI:0403”(colocalization)	0.650
SHLD3	TP53BP1	psi-mi:“MI:0403”(colocalization)	0.380
MAD2L2		psi-mi:“MI:0914”(association)	0.350
SHLD3		psi-mi:“MI:0914”(association)	0.350
SHLD2	SHLD3	psi-mi:“MI:0914”(association)	0.350
SHLD1	SHLD3	psi-mi:“MI:0914”(association)	0.350
SHLD3	SHLD2	psi-mi:“MI:0914”(association)	0.350
TP53BP1	PSMD14	psi-mi:“MI:2364”(proximity)	0.270

ESM2 similar proteins: A1A5R8, A1L0Z4, A8PJX4, D3IUT5, O00443, P03120, P04015, P26546, P27223, P33411, P36085, P36792, Q02263, Q04383, Q08119, Q08AV6, Q08AX9, Q08D12, Q0JF48, Q4R9E9, Q5RA75, Q5RAY1, Q5RFV8, Q5TB30, Q5U4T8, Q5XGF1, Q5XH29, Q5ZKI7, Q61194, Q68FF0, Q69KN0, Q6CXP4, Q6DDJ5, Q6PUR7, Q6ZNX1, Q7Y1I7, Q81021, Q8CIG0, Q8IXR9, Q8K1K4

Diamond homologs: Q6ZNX1, Q9CZV2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

336 predictions. Top by Δscore:

Variant	Effect	Δscore
5:65624948:TTGA:T	donor_gain	0.9900
5:65625107:GT:G	donor_loss	0.9800
5:65625108:T:A	donor_loss	0.9800
5:65624912:A:AG	donor_gain	0.9700
5:65624913:G:GG	donor_gain	0.9700
5:65624949:TGAG:T	donor_gain	0.9600
5:65627993:T:G	donor_gain	0.9600
5:65625107:G:GG	donor_gain	0.9400
5:65625064:G:GT	donor_gain	0.9200
5:65627989:G:GG	donor_gain	0.9200
5:65627992:A:AG	donor_gain	0.9200
5:65624947:GT:G	donor_gain	0.9100
5:65627988:A:AG	donor_gain	0.9100
5:65625103:AAAGG:A	donor_loss	0.8700
5:65628478:G:GC	acceptor_gain	0.8600
5:65624897:GTTT:G	donor_gain	0.8500
5:65625109:A:C	donor_loss	0.8500
5:65624923:TTAAG:T	donor_loss	0.8100
5:65624924:TAAG:T	donor_loss	0.8100
5:65624925:AAG:A	donor_loss	0.8100
5:65624926:AGG:A	donor_loss	0.8100
5:65624927:GG:G	donor_loss	0.8100
5:65624928:G:C	donor_loss	0.8100
5:65624929:T:G	donor_loss	0.8100
5:65629462:CTTTA:C	acceptor_loss	0.8100
5:65629463:TTTA:T	acceptor_loss	0.8100
5:65629464:TTA:T	acceptor_loss	0.8100
5:65629465:TAGGT:T	acceptor_loss	0.8100
5:65629466:A:AC	acceptor_loss	0.8100
5:65629467:G:A	acceptor_loss	0.8100

AlphaMissense

1641 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:65630092:T:A	W169R	0.993
5:65630092:T:C	W169R	0.993
5:65630227:T:C	F214L	0.982
5:65630229:C:A	F214L	0.982
5:65630229:C:G	F214L	0.982
5:65630191:G:C	A202P	0.978
5:65630094:G:C	W169C	0.977
5:65630094:G:T	W169C	0.977
5:65630093:G:C	W169S	0.971
5:65630085:A:C	R166S	0.969
5:65630085:A:T	R166S	0.969
5:65630140:T:A	W185R	0.967
5:65630140:T:C	W185R	0.967
5:65630192:C:A	A202D	0.967
5:65629699:T:C	F38L	0.964
5:65629701:T:A	F38L	0.964
5:65629701:T:G	F38L	0.964
5:65630150:T:C	L188P	0.964
5:65630267:T:C	L227P	0.962
5:65629981:T:A	W132R	0.961
5:65629981:T:C	W132R	0.961
5:65629864:T:C	F93L	0.958
5:65629866:T:A	F93L	0.958
5:65629866:T:G	F93L	0.958
5:65629708:T:A	W41R	0.957
5:65629708:T:C	W41R	0.957
5:65630267:T:A	L227H	0.957
5:65630185:T:C	C200R	0.954
5:65630219:T:A	I211K	0.954
5:65630230:T:C	C215R	0.951

dbSNP variants (sampled 300 via entrez): RS1000077933 (5:65626539 C>T), RS1000155940 (5:65626758 T>C,G), RS1000647913 (5:65631298 A>T), RS1000790050 (5:65627107 G>A,C), RS1000971189 (5:65626809 T>C), RS1001018670 (5:65631075 G>C), RS1001337131 (5:65625804 C>T), RS1002255804 (5:65624695 A>C,T), RS1002450132 (5:65630648 T>C), RS1002481130 (5:65630959 A>G), RS1002735790 (5:65624992 C>A,G,T), RS1003085761 (5:65623037 G>A), RS1003330210 (5:65623981 C>T), RS1003453608 (5:65629300 A>G), RS1004277086 (5:65623766 GT>G)

Disease associations

OMIM: gene MIM:618030 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010701_121	Cortical surface area (MOSTest)	6.000000e-11
GCST010702_62	Subcortical volume (MOSTest)	6.000000e-12
GCST010703_77	Brain morphology (MOSTest)	2.000000e-16

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

2 total (human), top 2 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects binding, increases reaction	1
Tobacco Smoke Pollution	increases expression	1

Clinical trials (associated diseases)

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