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

Abstract

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 ®broblasts exhibit increased post-replicative genomic instability, G 2 /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, speci®c female embryonic lethality is observed in parp-1 +/± parp-2 ±/± mutants at E9.5. Metaphase analyses of E8.5 embryonic ®broblasts highlight a speci®c 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.

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

“…The DBD is formed by a SAP domain that is responsible for DNA binding [20], and contains a functional nuclear localization signal (NLS) [21] and a nucleolar localization signal (NoLS) [22]. A caspase-3 cleavage site defines the border between the DBD and domain E, which is homologous to the caspase-3 site in the E domain of PARP-1 [23]. Domain E serves as a homodimerization interface, an automodification domain and a protein-protein interaction domain as well [24].…”

“…Upon the induction of DNA damage (ionizing irradiation, or laser irradiation), PARP-2 accumulates at the damage foci [35] with a slower kinetics than PARP-1, and PARP-2 persisted longer at DNA damage sites [36]. In murine embryonic fibroblasts (MEFs) the loss of PARP-2 leads to hypersensitivity to ionizing irradiation and cell cycle arrest in G1 [23], although PARP-2 -/-cells are less sensitive to ionizing radiation than PARP-1 -/-cells [23,24]. In line with these observations female lethality due to X chromosome instability was observed in…”

“…Moreover, PARP-2 interacts with numerous members of the BER machinery such as XRCC1, PARP-1, DNA pol and DNA ligase III [18] that further signifies its importance in BER. It is tempting to hypothesize that the early embryonic lethality of the PARP-1/PARP-2 double knockout mice [23] might be due to the strong impairment of DNA repair processes.…”

Differential Effect of PARP-2 Deletion on Brain Injury after Focal and Global Cerebral Ischemia

“…Chimeric offspring (129Sv/C57Bl/6) were subsequently backcrossed once to C57Bl/6 mice. The genotype of all mice was determined by polymerase chain reaction (PCR), as previously published (Ménissier de Murcia et al, 2003). Mice lacking PARP-2 display no visible abnormal phenotype by 18 months of life and are not tumor prone (Ménissier de Murcia et al, 2003).…”

“…Both enzymes initiate immediate, transient modification of nuclear proteins, leading to cell cycle arrest and DNA repair (D'Amours et al, 1999;Huber et al, 2004;Schreiber et al, 2002;Virag and Szabó , 2002). Thus, both enzymes play an important role in maintenance of genomic integrity, with both overlapping and redundant functions (Ménissier de Murcia et al, 2003). However, PARP-2 has been thought to be the less active isoform, contributing only 5% to 10% of total PARP activity in response to DNA damage (Amé et al, 1999;Schreiber et al, 2002).…”