Open AccessCaspase-2 regulates S-phase cell cycle events to protect from DNA damage accumulation independent of apoptosis
Author(s) -
Ashley Boice,
Karla E. Rojas López,
Raj K. Pandita,
Matthew S. Parsons,
Chloé I Charendoff,
Vijay Charaka,
Alexandre F. Carisey,
Tej K. Pandita,
Lisa BouchierHayes
Publication year - 2021
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/s41388-021-02085-w
Subject(s) - biology , dna damage , microbiology and biotechnology , cell cycle , dna replication , dna repair , caspase 2 , s phase , dna re replication , cell cycle checkpoint , caspase , apoptosis , cell division , proliferating cell nuclear antigen , control of chromosome duplication , eukaryotic dna replication , dna , cell , programmed cell death , genetics
In addition to its classical role in apoptosis, accumulating evidence suggests that caspase-2 has non-apoptotic functions, including regulation of cell division. Loss of caspase-2 is known to increase proliferation rates but how caspase-2 is regulating this process is currently unclear. We show that caspase-2 is activated in dividing cells in G1-phase of the cell cycle. In the absence of caspase-2, cells exhibit numerous S-phase defects including delayed exit from S-phase, defects in repair of chromosomal aberrations during S-phase, and increased DNA damage following S-phase arrest. In addition, caspase-2-deficient cells have a higher frequency of stalled replication forks, decreased DNA fiber length, and impeded progression of DNA replication tracts. This indicates that caspase-2 protects from replication stress and promotes replication fork protection to maintain genomic stability. These functions are independent of the pro-apoptotic function of caspase-2 because blocking caspase-2-induced cell death had no effect on cell division, DNA damage-induced cell cycle arrest, or DNA damage. Thus, our data supports a model where caspase-2 regulates cell cycle and DNA repair events to protect from the accumulation of DNA damage independently of its pro-apoptotic function.