Replication Through Repetitive DNA Elements and Their Role in Human Diseases

Abstract

Human cells contain various repetitive DNA sequences, which can be a challenge for the DNA replication machinery to travel through and replicate correctly. Repetitive DNA sequence can adopt non-B DNA structures, which could block the DNA replication. Prolonged stalling of the replication fork at the endogenous repeats in human cells can have severe consequences such as genome instability that includes repeat expansions, contractions, and chromosome fragility. Several neurological and muscular diseases are caused by a repeat expansion. Furthermore genome instability is the major cause of cancer. This chapter describes some of the important classes of repetitive DNA sequences in the mammalian genome, their ability to form secondary DNA structures, their contribution to replication fork stalling, and models for repeat expansion as well as chromosomal fragility. Included in this chapter are also some of the strategies currently employed to detect changes in DNA replication and proteins that could prevent the repeat-mediated disruption of DNA replication in human cells. Additionally summarized are the consequences of repeat-associated perturbation of the DNA replication, which could lead to specific human diseases.

Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome

“…Non‐B DNA motifs are short genomic DNA sequences, that is <100 nucleotides in size, that have the potential to adopt non‐B DNA structure. Such motifs have been associated with genomic instability in several previous studies (Bacolla & Wells, ; Boyer, Grgurevic, Cazaux, & Hoffmann, ; Chen et al, ; Madireddy & Gerhardt, ; Oren et al, ; Wang & Vasquez, ; Wells, ; Wojciechowska, Napierala, Larson, & Wells, ; Zhao, Bacolla, Wang, & Vasquez, ). In particular, STRs, and IRs (including palindromic or potential cruciform forming sequences) have been found to be enriched near recurrent and nonrecurrent deletion CNV breakpoints (Akgun et al, ; Chen et al, ; Oren et al, ).…”

A Chromosome-Scale Assembly of the Asian Honeybee Apis cerana Genome

“…Repeat sequences are widely distributed in higher organisms and play an important role in regulation of gene transcription (Fotsing et al, 2019;Wu et al, 2019), DNA replication (Madireddy and Gerhardt, 2017), and so on. We analyzed categories and proportions of repeat sequences in this new assembly.…”

Centromeres under Pressure: Evolutionary Innovation in Conflict with Conserved Function

“…These and other possible arrangements for three-dimensional DNA folding are expected to directly hinder the replication process as physical barriers. These impediments can also lead to the lower affinity of DNA polymerase for the newly synthetized strand, causing out of register “replication slippage” ( Figure 3 C) [ 182 ]. Replication slippage has been speculated to contribute to centromere repeat amplification, and can provoke either replication fork stalling or collapse, generating a DSB and further promoting mutagenesis [ 183 , 184 ].…”