Entrenching role of cell cycle checkpoints and autophagy for maintenance of genomic integrity

Abstract

Genomic integrity of the cell is crucial for the successful transmission of genetic information to the offspring and its survival. Persistent DNA damage induced by endogenous and exogenous agents leads to various metabolic manifestations. To combat this, eukaryotes have developed complex DNA damage response (DDR) pathway which senses the DNA damage and activates an arsenal of enzymes for the repair of damaged DNA. The active pathways for DNA repair are nucleotide excision repair (NER), base excision repair (BER) and mismatch repair (MMR) for single-strand break repair whereas homologous recombination (HR) and non-homologous end-joining (NHEJ) for double-strand break repair. OGG1 is a DNA glycosylase which initiates BER while Mre11-Rad50-Nbs1 (MRN) protein complex is the primary responder to DSBs which gets localized to damage sites. DNA damage response is meticulously executed by three related kinases: ATM, ATR, and DNA-PK. ATM- and ATR-dependent phosphorylation of p53, Chk1, and Chk2 regulate the G1/S, intra-S, or G2/M checkpoints of the cell cycle, respectively. Autophagy is an evolutionarily conserved process that plays a pivotal role in the regulation of DNA repair and maintains the cellular homeostasis. Genotoxic stress-induced altered autophagy occurs in a P53 dependent manner which is also the master regulator of genotoxic stress. A plethora of proteins involved in autophagy is regulated by p53 which involve DRAM, DAPK, and AMPK. As evident, the mtDNA is more prone to damage than nuclear DNA because of its close proximity to the site of ROS generation. Depending on the extent of damage either the repair mechanism or mitophagy gets triggered. SIRT1 is the master regulator which directs the stress response to mitophagy. Nix, a LC3 adapter also participates in Parkin mediated mitophagy. This review highlights the intricate crosstalks between DNA damage and cell cycle checkpoints activation. The DNA damage mediated regulation of autophagy and mitophagy is also reviewed in detail.

Keywords: Autophagy; Cell-cycle checkpoints; DDR and repair pathways; DNA damage.