RT Journal Article
SR Electronic
T1 ATM phosphorylates PP2A subunit A resulting in nuclear export and spatiotemporal regulation of the DNA damage response
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.29.458108
DO 10.1101/2021.08.29.458108
A1 Amrita Sule
A1 Sarah E. Golding
A1 Syed F. Farhan
A1 James Watson
A1 Mostafa H. Ahmed
A1 Glen E. Kellogg
A1 Tytus Bernas
A1 Sean Koebley
A1 Jason C. Reed
A1 Lawrence F. Povirk
A1 Kristoffer Valerie
YR 2021
UL http://biorxiv.org/content/early/2021/08/29/2021.08.29.458108.abstract
AB Ataxia telangiectasia mutated (ATM) is a serine-threonine protein kinase and important regulator of the DNA damage response (DDR). One critical ATM target is the structural subunit A (PR65) of protein phosphatase 2A (PP2A), known to regulate diverse cellular processes such as mitosis and cell growth as well as dephosphorylating many proteins during the recovery from the DDR. We generated mouse embryonic fibroblasts expressing PR65-WT, -S401A (cannot be phosphorylated), and -S401D (phosphomimetic) transgenes. Significantly, S401 mutants exhibited extensive chromosomal aberrations, impaired DNA double-strand break (DSB) repair and underwent increased mitotic catastrophe after radiation. Our study demonstrates that the phosphorylation of a single, critical PR65 amino acid (S401) by ATM fundamentally controls the DDR, and balances DSB repair quality, cell survival and growth by spatiotemporal PR65 nuclear-cytoplasmic shuttling mediated by the nuclear export receptor CRM1.Competing Interest StatementThe authors have declared no competing interest.