RT Journal Article
SR Electronic
T1 Phosphorylation Status Of MUS81 Is A Modifier Of Olaparib Sensitivity In BRCA2-Deficient Cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.08.13.503764
DO 10.1101/2022.08.13.503764
A1 Francesca Blandino
A1 Eva Malacaria
A1 Carolina Figlioli
A1 Alessandro Noto
A1 Giusj Monia Pugliese
A1 Annapaola Franchitto
A1 Pietro Pichierri
YR 2023
UL http://biorxiv.org/content/early/2023/03/22/2022.08.13.503764.abstract
AB The MUS81 complex is crucial for preserving genome stability through resolution of branched DNA intermediates in mitosis and also for the processing of deprotected replication forks in BRCA2-deficient cells. Because of the existence of two different MUS81 complexes in mammalian cells that act in M or S-phase, whether and how the PARPi sensitivity of BRCA2-deficient cells is affected by loss of MUS81 function is unclear.Here, using a mutant of MUS81 that impairs its function in M-phase, we show that viability of BRCA2-deficient cells but not their PARPi sensitivity requires a fully-functional MUS81 complex in mitosis. In contrast, expression of a constitutively-active MUS81 is sufficient to confer PARPi resistance. From a mechanistic point of view, our data indicates that deregulated action of the mitotic active form of MUS81 in S-phase leads to the cleavage of stalled replication forks before their reversal, bypassing fork deprotection, and engaging a Polθ-dependent DSBs repair.Collectively, our findings describe a novel mechanism leading to PARPi resistance that involves unscheduled MUS81-dependent cleavage of intact, unreversed replication forks. Since this cleavage occurs mimicking the phosphorylated status of S87 of MUS81, our data suggest that hyperphosphorylation of this residue in S-phase might represent a novel biomarker to identify resistance to PARPi.Competing Interest StatementThe authors have declared no competing interest.