RNA demethylase ALKBH5 regulates cell cycle progression in DNA damage response

Abstract

Abstract RNA N6-methyladenosine (m6A) modification plays a crucial role in the DNA damage response, while the detailed mechanisms remain to be explored. In this study, we report the involvement of the m6A demethylase ALKBH5 in X-ray-induced DNA damage response. Depletion of ALKBH5 reduces X-ray-induced DNA damage, induces G2/M phase arrest and reduces cell apoptosis. RNA sequencing and m6A sequencing analysis reveal that ALKBH5 removes m6A modifications from its target mRNAs and suppresses their expression. A subset of mRNAs encoding cyclin dependent kinase inhibitors, such as CDKN1A and CDKN2B, show increased stability and expression upon ALKBH5 knockdown. Subsequently, the upregulation of CDKN1A and CDKN2B contributes to G2/M phase arrest to facilitate DNA repair. Our findings unveil the epigenetic regulation of cell cycle checkpoint by ALKBH5 in X-ray-induced DNA damage, offering potential targets for DNA damage-based therapy for cancers.