Highlights d Radiogenetic profiling identifies ERCC6L2 as a major determinant of IR response d Loss of ERCC6L2 restores HR and causes PARPi resistance in BRCA1-deficient cells d ERCC6L2 contributes to NHEJ, possibly through its interaction with SFPQ d Patients with ERCC6L2-mutated UCEC show better survival upon RT

Tumor cells show widespread genetic alterations that change the expression of genes driving tumor progression, including genes that maintain genomic integrity. In recent years, it has become clear that tumors frequently reactivate genes whose expression is typically restricted to germ cells. As germ cells have specialized pathways to facilitate the exchange of genetic information between homologous chromosomes, their aberrant regulation influences how cancer cells repair DNA double strand breaks (DSB). This drives genomic instability and affects the response of tumor cells to anticancer therapies. Since meiotic genes are usually transcriptionally repressed in somatic cells of healthy tissues, targeting aberrantly expressed meiotic genes may provide a unique opportunity to specifically kill cancer cells whilst sparing the non-transformed somatic cells. In this review, we highlight meiotic genes that have been reported to affect DSB repair in cancers derived from somatic cells. A better understanding of their mechanistic role in the context of homology-directed DNA repair in somatic cancers may provide useful insights to find novel vulnerabilities that can be targeted.

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The PSMC3IP-MND1 heterodimer promotes RAD51 and DMC1-dependent D-loop formation during meiosis in yeast and mammalian organisms. For this purpose, it catalyzes the DNA strand exchange activities of the recombinases. Interestingly, in a panel of genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, we found that depletion of either PSMC3IP or MND1 caused sensitivity to clinical Poly (ADP-Ribose) Polymerase inhibitors (PARPi). A retroviral mutagenesis screen in mitotic cells also identified PSMC3IP and MND1 as genetic determinants of ionizing radiation sensitivity. The role PSMC3IP and MND1 play in preventing PARPi sensitivity in mitotic cells appears to be independent of a previously described role in alternative lengthening of telomeres (ALT). PSMC3IP or MND1 depleted cells accumulate toxic RAD51 foci in response to DNA damage, show impaired homology-directed DNA repair, and become PARPi sensitive, even in cells lacking both BRCA1 and TP53BP1. Although replication fork reversal is also affected, the epistatic relationship between PSMC3IP-MND1 and BRCA1/BRCA2 suggests that the abrogated D-loop formation is the major cause of PARPi sensitivity. This is corroborated by the fact that a PSMC3IP p.Glu201del D-loop formation mutant associated with ovarian dysgenesis fails to reverse PARPi sensitivity. These observations suggest that meiotic proteins such as MND1 and PSMC3IP could have a greater role in mitotic cells in determining the response to therapeutic DNA damage.