Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse

AUTOR(ES)

Ménissier de Murcia, Josiane

FONTE

Oxford University Press

RESUMO

The DNA damage-dependent poly(ADP-ribose) polymerases, PARP-1 and PARP-2, homo- and heterodimerize and are both involved in the base excision repair (BER) pathway. Here, we report that mice carrying a targeted disruption of the PARP-2 gene are sensitive to ionizing radiation. Following alkylating agent treatment, parp-2–/–-derived mouse embryonic fibroblasts exhibit increased post-replicative genomic instability, G2/M accumulation and chromosome mis-segregation accompanying kinetochore defects. Moreover, parp-1–/–parp-2–/– double mutant mice are not viable and die at the onset of gastrulation, demonstrating that the expression of both PARP-1 and PARP-2 and/or DNA-dependent poly(ADP-ribosyl) ation is essential during early embryogenesis. Interestingly, specific female embryonic lethality is observed in parp-1+/–parp-2–/– mutants at E9.5. Meta phase analyses of E8.5 embryonic fibroblasts highlight a specific instability of the X chromosome in those females, but not in males. Together, these results support the notion that PARP-1 and PARP-2 possess both overlapping and non-redundant functions in the maintenance of genomic stability.

Documentos Relacionados

• Early Embryonic Lethality in PARP-1 Atm Double-Mutant Mice Suggests a Functional Synergy in Cell Proliferation during Development
• Functional Interaction between Poly(ADP-Ribose) Polymerase 2 (PARP-2) and TRF2: PARP Activity Negatively Regulates TRF2
• PARP-1 Deficiency Increases the Severity of Disease in a Mouse Model of Multiple Sclerosis*
• A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage
• PARP-1 transcriptional activity is regulated by sumoylation upon heat shock