The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK; Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; Departement of Biomedical Research (DBMR), Cancer Therapy Resistance Cluster, University of Bern, 3012 Bern, Switzerland.
Cell Rep. 2023 May 30;42(5):112484. doi: 10.1016/j.celrep.2023.112484. Epub 2023 May 9.
The PSMC3IP-MND1 heterodimer promotes meiotic D loop formation before DNA strand exchange. In genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, depletion of PSMC3IP or MND1 causes sensitivity to poly (ADP-Ribose) polymerase inhibitors (PARPi) used in cancer treatment. PSMC3IP or MND1 depletion also causes ionizing radiation sensitivity. These effects are independent of PSMC3IP/MND1's role in mitotic alternative lengthening of telomeres. 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. Epistasis between PSMC3IP-MND1 and BRCA1/BRCA2 defects suggest that abrogated D loop formation is the cause of PARPi sensitivity. Wild-type PSMC3IP reverses PARPi sensitivity, whereas a PSMC3IP p.Glu201del mutant associated with D loop defects and ovarian dysgenesis does not. These observations suggest that meiotic proteins such as MND1 and PSMC3IP have a greater role in mitotic DNA repair.
PSMC3IP-MND1 异二聚体在 DNA 链交换前促进减数分裂 D 环形成。在有丝分裂细胞的全基因组规模的 CRISPR-Cas9 诱变和干扰筛选中，PSMC3IP 或 MND1 的耗竭导致对用于癌症治疗的聚（ADP-核糖）聚合酶抑制剂（PARPi）敏感。PSMC3IP 或 MND1 的耗竭也会导致电离辐射敏感。这些效应独立于 PSMC3IP/MND1 在有丝分裂端粒的替代性延长中的作用。PSMC3IP 或 MND1 耗竭的细胞在响应 DNA 损伤时积累有毒的 RAD51 焦点，显示同源定向 DNA 修复受损，并对 PARPi 敏感，即使在缺乏 BRCA1 和 TP53BP1 的细胞中也是如此。PSMC3IP-MND1 与 BRCA1/BRCA2 缺陷之间的上位性表明，D 环形成的中断是 PARPi 敏感性的原因。野生型 PSMC3IP 逆转了 PARPi 敏感性，而与 D 环缺陷和卵巢发育不良相关的 PSMC3IP p.Glu201del 突变体则没有。这些观察结果表明，减数分裂蛋白（如 MND1 和 PSMC3IP）在有丝分裂 DNA 修复中具有更大的作用。
