Cell Cycle and DNA Damage Response in Postmitotic Neurons

Abstract

Cellular DNA copes with constant exposure to different hazards, environmental and intrinsic. This leads to DNA lesions which interfere with transcription and replication and if not repaired or repaired incorrectly, can produce mutations or large-scale genome aberrations that may lead to cell malfunction or cell death and contribute to different pathologies (Jackson, 2009; Sancar et al., 2004). For this reason, virtually every organism is equipped with highly conserved genome surveillance network known as the DNA damage response (DDR) whose function is to sense genome damage and activate several downstream pathways, including cell cycle checkpoints, DNA repair and apoptotic signaling (Rouse & Jackson, 2002; Zhou & Elledge., 2000). The DDR has been investigated mainly in mitotic cells, in which the cell cycle checkpoints are a major contributor to the DDR, required for DNA repair (Stracker et al., 2008). Not much is known about the DDR in postmitotic neurons. It is known, however, that all eukaryotic DNA repair systems operating in proliferating cells also operate in neurons (Fishel et al., 2007; Lee & McKinnon, 2007; Sharma, 2007; Weissman et al., 2007; Wilson, & McNeill, 2007) and that dysfunctional DDR plays an important role in neurodegeneration and is associated with syndromes (e.g. ataxia telangiectasia) characterized by neurological abnormalities (Barzilai, 2010; Rass et al., 2007; Shiloh, 2003, 2006). This suggests the importance of DDR for postmitotic neurons. While the cell cycle checkpoints are part of DDR involved in DNA repair, apoptotic signaling, and cell fate decisions in mitotic cells, their contribution to the DDR of postmitotic neurons remains unclear. Nonetheless, evidence accumulates that DNA damage-initiated apoptosis of postmitotic neurons is associated with cell cycle signaling. Recently, we have demonstrated the importance of the cell cycle activation for DNA repair in postmitotic neurons (Tomashevski et al., 2010). This suggests that the expression of cell-cycle markers (Schmetsdorf et al., 2007, 2009) and DNA repair activity (Sharma, 2007) observed in the brain under physiological conditions may contribute to DNA repair. The involvement of the cell cycle machinery to both DNA repair and DNA damage-initiated apoptosis in postmitotic neurons suggests a potential function of cell cycle checkpoints in the DDR of these postmitotic cells. This review focuses on the DDR of postmitotic neurons in the context of what is known about the DDR of mitotic cells.