Regulation of Replication Stress in Alternative Lengthening of Telomeres by Fanconi Anaemia Protein.

Duda Li,Kailong Hou,Shuting Jia,Ke Zhang

doi:10.3390/genes13020180

Duda Li, Kailong Hou + Show 2 more

Open Access

https://doi.org/10.3390/genes13020180

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Journal: Genes	Publication Date: Jan 20, 2022
Citations: 4	License type: CC BY 4.0

Affiliation: Kunming University of Science and Technology

Abstract

Fanconi anaemia (FA)-related proteins function in interstrand crosslink (ICL) repair pathways and multiple damage repair pathways. Recent studies have found that FA proteins are involved in the regulation of replication stress (RS) in alternative lengthening of telomeres (ALT). Since ALT cells often exhibit high-frequency ATRX mutations and high levels of telomeric secondary structure, high levels of DNA damage and replicative stress exist in ALT cells. Persistent replication stress is required to maintain the activity of ALT mechanistically, while excessive replication stress causes ALT cell death. FA proteins such as FANCD2 and FANCM are involved in the regulation of this balance by resolving or inhibiting the formation of telomere secondary structures to stabilize stalled replication forks and promote break-induced repair (BIR) to maintain the survival of ALT tumour cells. Therefore, we review the role of FA proteins in replication stress in ALT cells, providing a rationale and direction for the targeted treatment of ALT tumours.

Highlights

Introduction in Alternative Lengthening ofTelomeres are specialized ribonucleoprotein structures in eukaryotic linear chromosome ends, the maintenance of which is critical for the genomic stability and sustained survival of proliferating cells [1,2,3]
It has been determined that there are high levels of secondary structure and replication stress in alternative lengthening of telomeres (ALT) cells, accompanied by telomere loss and high levels of telomeric sister chromatid exchange (T-SCE), which demonstrates that these replication stresses are required for ALT activation [61,62,63]
This paper summarizes the mechanisms of the occurrence and maintenance of ALT

Summary

Source of Replication Stress of the ALT Telomeres

Studies found higher replication levels of stress and damage to telomeres compared to telomerase-dependent tumour cells, which is thought to be an activation signal of the ALT pathway and can promote elongation of ALT telomeres [37]. Dysfunction of ATRX promotes CFS expression and TERRA transcription and suppresses the unfolding of the G4 quadruplex and R-loop on ALT telomeres, contributing to the accumulation of telomeric secondary structures that hinder replication fork progression and induce the accumulation of replication stress [48,49,50]. In response to higher levels of replication stress, endonucleases such as BLM in ALT cells are recruited to telomeres to induce stalled replication fork collapse and DNA lesion, activating BIR that promote telomere elongation and cell survival [15,37]. Regulation of replication stress identifies the activity of the ALT machinery and is critical for ALT cell viability

FANCM Unfolds the R-Loop and Stalled Replication Forks to Inhibit Excessive

Regulation of Replication Stress in ALT Cells by Other FA Proteins

Discussion