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bioRxiv · 10.1101/2021.07.15.452469

RAD51AP1 compensates for the loss of RAD54 in homology-directed DNA repair

Selemenakis, P.·Sharma, N.·Kwon, Y.·Uhrig, M.·Sung, P.·Wiese, C.
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Abstract

Homologous recombination (HR) is a complex DNA damage repair pathway and an attractive target of inhibition in anti-cancer therapy. To help guide the development of efficient HR inhibitors, it is critical to identify compensatory sub-pathways. In this study, we describe a novel synthetic interaction between RAD51AP1 and RAD54, two structurally unrelated proteins that function downstream of the RAD51 recombinase in HR. We show that deletion of both RAD51AP1 and RAD54 synergistically sensitizes human cancer cell lines to treatment with a Poly(adenosine 5 s-diphosphate-ribose) polymerase inhibitor, to the DNA inter-strand crosslinking agent mitomycin C, and to hydroxyurea, which stalls the progression of DNA replication forks. We infer that HR-directed anti-cancer treatment modalities shall consider this intra-pathway functional overlap, and we hypothesize that in cancerous cells the simultaneous inactivation of both RAD54 and RAD51AP1 will accentuate tumor kill.

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Selemenakis, P., Sharma, N., Kwon, Y., Uhrig, M., Sung, P., Wiese, C.. 2021-07-15. RAD51AP1 compensates for the loss of RAD54 in homology-directed DNA repair. https://doi.org/10.1101/2021.07.15.452469

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