抄録
Cancer genome testing routinely reports driver alterations, mutational signatures, and DNA repair states, yet
key clinical phenotypes—tumor behavior, relapse risk, and chemoresistance—are not fully explained by genotype
alone. Deleted in split-hand/split-foot 1 (DSS1) is a small, acidic, intrinsically disordered protein conserved
across eukaryotes and shared by several large multiprotein assemblies, making it a plausible functional modifier
of these phenotypes. This review summarizes DSS1 biology from the perspective of clinical laboratory medicine,
focusing on how DSS1 links RNA metabolism, R-loop homeostasis, and homologous recombination repair
(HRR) and how this linkage may inform biomarker development. Mechanistically, DSS1 behaves as a stabilizing
“molecular glue” in protein complexes and serves as a core component of RNA export/quality-control modules,
including TREX-2 and the TREX-2.1/REX complex, which regulate co-transcriptional messenger ribonucleoprotein
remodeling, nuclear export, and RNA surveillance—processes closely tied to R-loop (DNA:RNA hybrid)
control and transcription-coupled DNA damage. DSS1 is also an obligate cofactor of BRCA2: DSS1 binding stabilizes
BRCA2, improves its solubility, and limits off-target interactions, supporting repair-competent BRCA2 in
the nucleus. We then review clinicopathological evidence that DSS1 dysregulation correlates with cancer behavior,
including shorter relapse-free survival and a chemoresistant phenotype. Finally, we propose that DSS1-low,
BRCA-proficient tumors may acquire BRCAness, providing a rationale for PARP inhibitor responses beyond current
BRCA-focused companion diagnostics, and we outline how standardized DSS1 measurement (mRNA and/
or protein), integrated with BRCA status and other HRR-related signatures, could refine molecular testing and
therapeutic stratification in routine practice.
