DNA damage responses that enhance resilience to replication stress.
Kazumasa YoshidaMasatoshi FujitaPublished in: Cellular and molecular life sciences : CMLS (2021)
During duplication of the genome, eukaryotic cells may experience various exogenous and endogenous replication stresses that impede progression of DNA replication along chromosomes. Chemical alterations in template DNA, imbalances of deoxynucleotide pools, repetitive sequences, tight DNA-protein complexes, and conflict with transcription can negatively affect the replication machineries. If not properly resolved, stalled replication forks can cause chromosome breaks leading to genomic instability and tumor development. Replication stress is enhanced in cancer cells due, for example, to the loss of DNA repair genes or replication-transcription conflict caused by activation of oncogenic pathways. To prevent these serious consequences, cells are equipped with diverse mechanisms that enhance the resilience of replication machineries to replication stresses. This review describes DNA damage responses activated at stressed replication forks and summarizes current knowledge on the pathways that promote faithful chromosome replication and protect chromosome integrity, including ATR-dependent replication checkpoint signaling, DNA cross-link repair, and SLX4-mediated responses to tight DNA-protein complexes that act as barriers. This review also focuses on the relevance of replication stress responses to selective cancer chemotherapies.
Keyphrases
- dna damage
- dna repair
- oxidative stress
- circulating tumor
- induced apoptosis
- transcription factor
- cell free
- climate change
- healthcare
- blood brain barrier
- gene expression
- depressive symptoms
- young adults
- high frequency
- copy number
- genome wide
- dna methylation
- signaling pathway
- papillary thyroid
- binding protein
- cell death
- high resolution
- nucleic acid
- lymph node metastasis