SHLD2

Review rationale: The horse SHLD2 gene carries this term on its canonical product A0A9L0TUF0; whether this product carries it is unresolved. Human SHLD2 promotes NHEJ as part of shieldin: its N-terminus binds SHLD3-REV7 for recruitment, and its C-terminal OB-fold module (SHLD2C) binds single-stranded DNA with SHLD1 to protect ends. A0A9L0RGD6 keeps the recruitment segment, OB folds A and B and the four zinc-ribbon cysteines of OB fold C, but conservation ends after horse residue ~811: its Pfam SHLD2 C-terminal match spans 733-804 (72 residues) against 772-935 (164 residues) in the canonical model, and it lacks the equivalent of human iso-1 731-835, the distal half of the SHLD1-interacting region (652-822). Human OB-fold point mutant m1 and the SHLD2S variant disrupting OB fold B still reach DSBs and assemble shieldin but fail to suppress HR, so the module is required. Neither mutation corresponds to this C-terminal truncation, and no experiment has tested whether a SHLD2 that keeps OB folds A, B and the zinc ribbon binds ssDNA or SHLD1. The missing segment is part of the required module, but its loss is not shown to abolish the function, and the retained recruitment and partial SHLD1-binding regions could still contribute. Neither positive refutation nor a fully accounted mechanism applies, so the call is uncertain.

Review rationale: HPA reports an additional actin-filament pool of human SHLD2, but the human SHLD2 review accepts only the main nucleoplasm location and no GO annotation or experiment supports actin association. The secondary signal is a single antibody-based observation with no known targeting mechanism, and family membership does not establish that the horse protein shares it. No PubMed literature links SHLD2 to actin. The term is absent from the horse gene's annotations and cannot be validated or refuted.

Review rationale: Human SHLD2 is recruited to DSBs via the 53BP1-RIF1 axis through its N-terminal SHLD3-REV7-binding segment, and human OB-fold mutants still localize to DSB sites, so recruitment does not depend on the C-terminal module this model has lost. A0A9L0RGD6 is in the single SHLD2 subfamily and keeps the N-terminal recruitment region, so the location transfers by orthology; this is an inference, not a horse observation. The horse SHLD2 gene already carries site of double-strand break (IBA and IEA) on its canonical product A0A9L0TUF0, so the prediction is correct but not novel.

Review rationale: Human SHLD2 is mainly nucleoplasmic by HPA immunofluorescence and relocalizes into nuclear damage foci. A0A9L0RGD6 is an orthologous SHLD2 model that keeps the N-terminal recruitment region, so the nuclear location transfers by orthology; this is an inference for horse. The horse SHLD2 gene already carries nucleoplasm (IEA ortholog transfer) on its canonical product A0A9L0TUF0, so the prediction is correct but not novel.

Review rationale: The horse SHLD2 gene carries this term on its canonical product A0A9L0TUF0; whether this product carries it is unresolved. Human SHLD2 suppresses HR by blocking end resection through ssDNA binding by the C-terminal SHLD2-SHLD1 OB-fold module (SHLD2C). OB-fold mutant m1 and the SHLD2S variant disrupting OB fold B localize to DSBs and assemble shieldin yet fail to suppress HR, so recruitment alone is not enough. A0A9L0RGD6 keeps the recruitment segment, OB folds A and B and the OB-fold-C zinc ribbon; its Pfam SHLD2 C-terminal match spans only 733-804 (72 residues) against 772-935 (164 residues) in the canonical model, and it lacks the distal half of the human SHLD1-interacting region, which is replaced by an unrelated Arg/Gly/Pro-rich tail. The tested human mutations differ from this C-terminal truncation, and whether the partial module still binds ssDNA or SHLD1 has not been measured. The anti-HR mechanism therefore depends on a module this product keeps only in part, and loss of the function is neither shown nor excluded, so the call is uncertain.

Review rationale: Shieldin loss impairs class-switch recombination in mammalian B cells, and the horse SHLD2 gene carries this term (IEA ortholog transfer) on its canonical product A0A9L0TUF0. SHLD2 contributes to CSR through NHEJ-promoting end protection by shieldin, which uses the N-terminal SHLD3-REV7 recruitment segment and the C-terminal SHLD2-SHLD1 OB-fold ssDNA-binding module. A0A9L0RGD6 keeps the recruitment segment, OB folds A and B and the OB-fold-C zinc ribbon, but has a truncated OB fold C (Pfam SHLD2 C-terminal match 733-804, 72 residues, against 772-935, 164 residues, in the canonical model) and lacks the distal half of the SHLD1-interacting region. No experiment shows that this truncation abolishes end protection or CSR, and no horse B-cell or CSR evidence exists. The missing segment does not fully account for the gene's role in CSR, and no evidence refutes the term for this product, so the call is uncertain.