RAD51 protects human cells from transcription-replication conflicts.

Rahul Bhowmick, Mads Lerdrup, Sampath Amitash Gadi, Giacomo G Rossetti, Manika I Singh, Ying Liu, Thanos D Halazonetis, Ian D Hickson

Molecular cell 2022 Sep 15

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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. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Rahul Bhowmick, Mads Lerdrup, Sampath Amitash Gadi, Giacomo G Rossetti, Manika I Singh, Ying Liu, Thanos D Halazonetis, Ian D Hickson. RAD51 protects human cells from transcription-replication conflicts. Molecular cell. 2022 Sep 15;82(18):3366-3381.e9