A game of substrates: replication fork remodeling and its roles in genome stability and chemo-resistance.

Julia Sidorova

doi:10.15698/cst2017.12.114

Abstract

During the hours that human cells spend in the DNA synthesis (S) phase of the cell cycle, they may encounter adversities such as DNA damage or shortage of nucleotides. Under these stresses, replication forks in DNA may experience slowing, stalling, and breakage. Fork remodeling mechanisms, which stabilize slow or stalled replication forks and ensure their ability to continue or resume replication, protect cells from genomic instability and carcinogenesis. Fork remodeling includes DNA strand exchanges that result in annealing of newly synthesized strands (fork reversal), controlled DNA resection, and cleavage of DNA strands. Defects in major tumor suppressor genes BRCA1 and BRCA2, and a subset of the Fanconi Anemia genes have been shown to result in deregulation in fork remodeling, and most prominently, loss of kilobases of nascent DNA from stalled replication forks. This phenomenon has recently gained spotlight as a potential marker and mediator of chemo-sensitivity in cancer cells and, conversely, its suppression - as a hallmark of acquired chemo-resistance. Moreover, nascent strand degradation at forks is now known to also trigger innate immune response to self-DNA. An increasingly sophisticated molecular description of these events now points at a combination of unbalanced fork reversal and end-resection as a root cause, yet also reveals the multi-layered complexity and heterogeneity of the underlying processes in normal and cancer cells.

Highlights

The three billion base pairs of the human genome are replicated in about six to eight hours of the S phase of the cell cycle
CONCLUDING REMARKS We hope to have shown that fork remodeling mechanisms emerge as balancing acts of many counteracting processes – a game of substrates that revolves around degradation versus protection of nascent DNA strands, and whose original main characters, MRE11 and RAD51, are surrounded by a whole cast of others
We have seen that many homologous recombination (HR) and non-homologous end joining (NHEJ) proteins are involved in fork protection and curiously, often in a somewhat “off-label” way that is not exactly identical to their roles in DNA repair

Summary

Introduction

The three billion base pairs of the human genome are replicated in about six to eight hours of the S phase of the cell cycle. DNA2/WRN and not MRE11 or EXO1 carried out resection in cases where nascent strand degradation was upregulated in BRCA-proficient cells [73].

Results

Conclusion