Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function.
J Cell Biol
; 218(2): 422-432, 2019 02 04.
Article
en En
| MEDLINE
| ID: mdl-30602538
ABSTRACT
53BP1 is a chromatin-associated protein that regulates the DNA damage response. In this study, we identify the TPX2/Aurora A heterodimer, nominally considered a mitotic kinase complex, as a novel binding partner of 53BP1. We find that TPX2/Aurora A plays a previously unrecognized role in DNA damage repair and replication fork stability by counteracting 53BP1 function. Loss of TPX2 or Aurora A compromises DNA end resection, BRCA1 and Rad51 recruitment, and homologous recombination. Furthermore, loss of TPX2 or Aurora A causes deprotection of stalled replication forks upon replication stress induction. This fork protection pathway counteracts MRE11 nuclease activity but functions in parallel to BRCA1. Strikingly, concurrent loss of 53BP1 rescues not only BRCA1/Rad51 recruitment but also the fork instability induced upon TPX2 loss. Our work suggests the presence of a feedback mechanism by which 53BP1 is regulated by a novel binding partner and uncovers a unique role for 53BP1 in replication fork stability.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Ciclo Celular
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Replicación del ADN
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Recombinación Homóloga
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Aurora Quinasa A
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Proteína 1 de Unión al Supresor Tumoral P53
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Proteínas Asociadas a Microtúbulos
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Mitosis
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Cell Biol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Macao