TY - JOUR
T1 - The CDK1-TOPBP1-PLK1 axis regulates the Bloom's syndrome helicase BLM to suppress crossover recombination in somatic cells
AU - Pogliano, Chiara Balbo
AU - Ceppi, Ilaria
AU - Giovannini, Sara
AU - Petroulaki, Vasiliki
AU - Palmer, Nathan
AU - Uliana, Federico
AU - Gatti, Marco
AU - Kasaciunaite, Kristina
AU - Freire, Raimundo
AU - Seidel, Ralf
AU - Altmeyer, Matthias
AU - Cejka, Petr
AU - Matos, Joao
N1 - Publisher Copyright:
© 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
PY - 2022/2
Y1 - 2022/2
N2 - Bloom's syndrome is caused by inactivation of the BLM helicase, which functions with TOP3A and RMI1-2 (BTR complex) to dissolve recombination intermediates and avoid somatic crossing-over. We show here that crossover avoidance by BTR further requires the activity of cyclin-dependent kinase-1 (CDK1), Polo-like kinase-1 (PLK1), and the DDR mediator protein TOPBP1, which act in the same pathway. Mechanistically, CDK1 phosphorylates BLM and TOPBP1 and promotes the interaction of both proteins with PLK1. This is amplified by the ability of TOPBP1 to facilitate phosphorylation of BLM at sites that stimulate both BLM-PLK1 and BLM-TOPBP1 binding, creating a positive feedback loop that drives rapid BLM phosphorylation at the G2-M transition. In vitro, BLM phosphorylation by CDK/PLK1/TOPBP1 stimulates the dissolution of topologically linked DNA intermediates by BLM-TOP3A. Thus, we propose that the CDK1-TOPBP1-PLK1 axis enhances BTR-mediated dissolution of recombination intermediates late in the cell cycle to suppress crossover recombination and curtail genomic instability.
AB - Bloom's syndrome is caused by inactivation of the BLM helicase, which functions with TOP3A and RMI1-2 (BTR complex) to dissolve recombination intermediates and avoid somatic crossing-over. We show here that crossover avoidance by BTR further requires the activity of cyclin-dependent kinase-1 (CDK1), Polo-like kinase-1 (PLK1), and the DDR mediator protein TOPBP1, which act in the same pathway. Mechanistically, CDK1 phosphorylates BLM and TOPBP1 and promotes the interaction of both proteins with PLK1. This is amplified by the ability of TOPBP1 to facilitate phosphorylation of BLM at sites that stimulate both BLM-PLK1 and BLM-TOPBP1 binding, creating a positive feedback loop that drives rapid BLM phosphorylation at the G2-M transition. In vitro, BLM phosphorylation by CDK/PLK1/TOPBP1 stimulates the dissolution of topologically linked DNA intermediates by BLM-TOP3A. Thus, we propose that the CDK1-TOPBP1-PLK1 axis enhances BTR-mediated dissolution of recombination intermediates late in the cell cycle to suppress crossover recombination and curtail genomic instability.
UR - http://www.scopus.com/inward/record.url?scp=85124152880&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abk0221
DO - 10.1126/sciadv.abk0221
M3 - Article
C2 - 35119917
AN - SCOPUS:85124152880
VL - 8
JO - Science Advances
JF - Science Advances
SN - 2375-2548
IS - 5
M1 - eabk0221
ER -