The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction

Abstract

The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for both cancer development and chemotherapy outcome. DDR represents the complex events that detect DNA lesions and activate signaling networks (cell cycle checkpoint induction, DNA repair, and induction of cell death). TP53, the guardian of the genome, governs the cell response, resulting in cell cycle arrest, DNA damage repair, apoptosis, and senescence. The mutational status of TP53 has an impact on DDR, and somatic mutations in this gene represent one of the critical events in human carcinogenesis. Telomere dysfunction in cells that lack p53-mediated surveillance of genomic integrity along with the involvement of DNA repair in telomeric DNA regions leads to genomic instability. While the role of individual players (DDR, telomere homeostasis, and TP53) in human cancers has attracted attention for some time, there is insufficient understanding of the interactions between these pathways. Since solid cancer is a complex and multifactorial disease with considerable inter- and intra-tumor heterogeneity, we mainly dedicated this review to the interactions of DNA repair, telomere homeostasis, and TP53 mutational status, in relation to (a) cancer risk, (b) cancer progression, and (c) cancer therapy.

Detection of disease‐causing mutations in prostate cancer by NGS sequencing

“…Lesions in TP53 are associated with more aggressive disease not only in PCa but also in many other solid tumors (Mateo et al, 2020;Vodicka et al, 2021) and our data support these observations.…”

Lung Fibroblasts from Idiopathic Pulmonary Fibrosis Patients Harbor Short and Unstable Telomeres Leading to Chromosomal Instability

“…The scored telomere abnormalities were (i) sister telomere loss, likely occurring in G2, and defined as a telomere signal-free end at a single chromatid [ 4 ], and (ii) telomere deletion, defined as the loss of two telomere signals on the same chromosome arm (likely resulting from the loss of one telomere in G1/S), an aberration considered to represent double strand breaks, leading to activation of DNA damage response [ 28 ]. Automatic scoring of these aberrations was performed using ChromoScore software.…”

Cyclin-Dependent Kinase Synthetic Lethality Partners in DNA Damage Response

“…TP53 is also involved in DSBR, where it interacts with replication protein A (RPA), RAD54, BRCA1, BRCA2, bloom syndrome protein (BLM), and WRN. Furthermore, non-homologous end joining (NHEJ) is also controlled by TP53, but its role is unclear [ 63 , 64 , 65 , 66 ].…”