RAD51 protects human cells from transcription-replication conflicts

• Published in: Molecular cell Vol. 82; no. 18; pp. 3366 - 3381.e9
• Main Authors: Bhowmick, Rahul, Lerdrup, Mads, Gadi, Sampath Amitash, Rossetti, Giacomo G., Singh, Manika I., Liu, Ying, Halazonetis, Thanos D., Hickson, Ian D.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 15.09.2022
• Subjects: common fragile sites; gene amplification in cancer; mitotic DNA synthesis; oncogene-induced DNA replication stress; replication fork protection; oncogene-induced DNA replication stress; mitotic DNA synthesis; replication fork protection; gene amplification in cancer; common fragile sites
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2022.07.010

Oncogene activation during tumorigenesis promotes DNA replication stress (RS), which subsequently drives the formation of cancer-associated chromosomal rearrangements. Many episodes of physiological RS likely arise due to conflicts between the DNA replication and transcription machineries operating simultaneously at the same loci. One role of the RAD51 recombinase in human cells is to protect replication forks undergoing RS. Here, we have identified a key role for RAD51 in preventing transcription-replication conflicts (TRCs) from triggering replication fork breakage. The genomic regions most affected by RAD51 deficiency are characterized by being replicated and transcribed in early S-phase and show significant overlap with loci prone to cancer-associated amplification. Consistent with a role for RAD51 in protecting against transcription-replication conflicts, many of the adverse effects of RAD51 depletion are ameliorated by inhibiting early S-phase transcription. We propose a model whereby RAD51 suppresses fork breakage and subsequent inadvertent amplification of genomic loci prone to experiencing TRCs. [Display omitted] •RAD51 is required to protect human cancer cells from transcription-replication conflicts•RAD51 is recruited to S-phase chromatin in a transcription-dependent manner•Replication fork protection by RAD51 prevents RAD52-dependent BIR during S/G2-phase•RAD51 protects genomic regions that are prone to amplification in human cancers In this study, Bhowmick et al. discover that RAD51 protects the human genome from transcription-replication conflicts. This new function of RAD51 potentially suppresses cancer genome amplification.