A role for the spindle assembly checkpoint in the DNA damage response
Palou, Roger (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Palou Marin, Gloria (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Garcia Quintana, David (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data:	2016
Resum:	Spontaneous DNA damage poses a continuous threat to genomic integrity. If unchecked, genotoxic insults result in genomic instability, a hallmark of cancer cells. In eukaryotic cells a DNA Damage Response (DDR) detects and responds to genotoxic stress, acting as an anti-cancer barrier in humans. Among other actions, the DDR blocks the segregation of incompletely replicated or damaged chromosomes, thus preventing aneuploidy. In a work aimed at better understanding such S-M control, we recently showed that cells block anaphase through different control pathways. The S phase checkpoint kinase Mec1/ATR inhibits mitotic Cyclin Dependent Kinase activity through effector kinases Swe1/Wee1 and Rad53/Chk2. Cells also stabilize the levels of Pds1/securin to block sister chromatid segregation in response to DNA damage. We show here that Pds1/securin abundance is still secured when the S phase checkpoint response is fully abrogated in mec1/ATR tel1/ATM double null mutants. When such cells are exposed to genotoxic stress, Pds1/securin is stabilized in a spindle assembly checkpoint (SAC) dependent manner. Disruption of the SAC and the S phase checkpoint together, allows chromosome segregation in the presence of DNA damage or replication stress. Our results place the SAC as a part of the DDR, which appears to count on different, independent control layers to preserve genomic integrity when chromosome replication is challenged.
Ajuts:	Ministerio de Economía y Competitividad BFU2011/28007 Ministerio de Economía y Competitividad BFU2015/68493-P
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	DNA damage response (DDR) ; Spindle assembly checkpoint (SAC) ; S Phase checkpoint ; Chromosome segregation ; Genomic instability ; Cyclin Dependent Kinase (Cdk1)
Publicat a:	Current Genetics, Vol. 63, Num. 2 (August 2016) , p. 275-280, ISSN 1432-0983

DOI: 10.1007/s00294-016-0634-y
PMID: 27488803

6 p, 1.1 MB

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