XPA is susceptible to proteolytic cleavage by cathepsin L during lysis of quiescent cells

Khan, Saman; Cvammen, William; Anabtawi, Nadeen; Choi, Jun-Hyuk; Kemp, Michael G.

doi:10.1016/j.dnarep.2021.103260

Cited by 1 publication

(1 citation statement)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here we re-visited a previous report that the generation of DSBs in UVB- irradiated quiescent cells is dependent on NER (Wakasugi et al, 2014) by using CRISPR/Cas9 genome editing to knockout XPA in HaCaT keratinocytes, which have been a useful model system for studying DNA damage responses in quiescent cells (Hutcherson and Kemp, 2019; Kemp, 2017; Kemp and Sancar, 2016; Khan et al, 2022; Shaj et al, 2020). In contrast to the previous study (Wakasugi et al, 2014), we find that DSBs are readily detected in UVB-irradiated cells ( Fig.…”

Section: Discussionmentioning

confidence: 98%

Rad51 inhibition sensitizes non-replicating quiescent cells to UVB radiation and transcription stress

Khan

Carpenter

Kemp

2022

Preprint

Self Cite

View full text Add to dashboard Cite

DNA damage induced by environmental, occupational, and chemotherapeutic compounds lead to a variety of cellular responses that are potentially impacted by the proliferation status of the cell. Using small molecule inhibitors of various DNA double-strand break (DSB) repair pathways in non-replicating, quiescent human cells exposed to UVB radiation, we unexpectedly observed a major role for the recombination protein Rad51 in promoting cell survival. In contrast to a previous report indicating a requirement for nucleotide excision repair (NER) in DSB formation after UV exposure in quiescent cells, we observed DSB formation and Rad51 function to be independent of NER. Moreover, our analyses of DNA damage response kinase signaling in quiescent cells identified protein substrates that were either dependent or independent of both NER and apoptotic signaling. Finally, we observed that Rad51 inhibition sensitized non-replicating quiescent cells to diverse genotoxic stressors, including those inducing DNA-RNA hybrids and inhibiting transcription. Thus, these findings clarify the mechanisms by which DSBs arise in non-replicating cells and highlight the important role of Rad51 in promoting quiescent cell survival in response to general genotoxic stress.

show abstract