Involvement of p53 in the Repair of DNA Double Strand Breaks: Multifaceted Roles of p53 in Homologous Recombination Repair (HRR) and Non-Homologous End Joining (NHEJ)

Abstract

p53 is a tumor suppressor protein that prevents oncogenic transformation and maintains genomic stability by blocking proliferation of cells harboring unrepaired or misrepaired DNA. A wide range of genotoxic stresses such as DNA damaging anti-cancer drugs and ionizing radiation promote nuclear accumulation of p53 and trigger its ability to activate or repress a number of downstream target genes involved in various signaling pathways. This cascade leads to the activation of multiple cell cycle checkpoints and subsequent cell cycle arrest, allowing the cells to either repair the DNA or undergo apoptosis, depending on the intensity of DNA damage. In addition, p53 has many transcription-independent functions, including modulatory roles in DNA repair and recombination. This chapter will focus on the role of p53 in regulating or influencing the repair of DNA double-strand breaks that mainly includes homologous recombination repair (HRR) and non-homologous end joining (NHEJ). Through this discussion, we will try to establish that p53 acts as an important linchpin between upstream DNA damage signaling cues and downstream cellular events that include repair, recombination, and apoptosis.

High mobility group (HMG) proteins: Modulators of chromatin structure and DNA repair in mammalian cells

“…p53 is important for monitoring and maintaining genomic integrity and has been demonstrated to be involved in many different repair processes including DSB repair [226], BER [224] and both global genomic [227][228][229] and region-specific NER [230]. The DNA-binding activity of p53 is essential for its biological function(s) both as a tumor suppressor and as a participant in DNA repair processes.…”

Identifying therapeutic targets in gastric cancer: the current status and future direction

“…Of these, ABC transporters may play a more significant role [48]. Menon and Povirk [49] found that ABC transporters in a group of NCI60 cells showed that more than half of the members of ABC transporters were linked with drug resistance.…”

“…Because of the mutations of oncogenes or tumor suppressor genes, some tumor cells can affect cell cycle arrest. In the presence of wild type p53, DNA damages trigger cell cycle arrest [49]. Mismatch repair (MMR) system is the key to maintain the integrity of the genome [52].…”

KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis

“…Several factors play important roles in regulating DNA damage-repair mechanisms, among them is the tumor suppressor p53. p53 acts as an important link between upstream signaling and activation of downstream signaling cascades depending on the extent of DNA damage, and can activate cell cycle arrest and allow the damage to be repaired or it could transactivate genes involved in the apoptotic machinery (50). Surprisingly, the primary effect of p53 on DNA repair mechanisms was shown be the inhibition of HRR and of NHEJ repair mechanisms (50).…”