Beyond DNA repair and chromosome instability\u2014Fanconi anaemia as a cellular senescence-associated syndrome

Anne Helbling-Leclerc,Cécile Garcin,Filippo Rosselli

doi:10.1038/s41418-021-00764-5

Abstract

Fanconi anaemia (FA) is the most frequent inherited bone marrow failure syndrome, due to mutations in genes encoding proteins involved in replication fork protection, DNA interstrand crosslink repair and replication rescue through inducing double-strand break repair and homologous recombination. Clinically, FA is characterised by aplastic anaemia, congenital defects and cancer predisposition. In in vitro studies, FA cells presented hallmarks defining senescent cells, including p53-p21 axis activation, altered telomere length, mitochondrial dysfunction, chromatin alterations, and a pro-inflammatory status. Senescence is a programme leading to proliferation arrest that is involved in different physiological contexts, such as embryogenesis, tissue remodelling and repair and guarantees tumour suppression activity. However, senescence can become a driving force for developmental abnormalities, aging and cancer. Herein, we summarise the current knowledge in the field to highlight the mutual relationships between FA and senescence that lead us to consider FA not only as a DNA repair and chromosome fragility syndrome but also as a “senescence syndrome”.

Highlights

● Activation of the p53-p21 and p16-pRb axes Driven by ATM/ATR, DNA damage response (DDR) signalling leads to cell cycle arrest by activating the p53-p21 and p16-pRb axes, which inhibit factors associated with the G1-S transition
The main downstream role of proteins of the FANC pathway is to repair cross-linked DNA and rescue delayed/ blocked replication forks while maintaining genomic stability, and the multiple clinical and cellular phenotypes that define Fanconi anaemia (FA) may be caused by a single factor with multiple tissue, cellular, biochemical and molecular consequences: the unscheduled activation of the senescence programme as a major consequence of the DNA damage-induced ATMp53-p21 axis
It is tempted to speculate that the prosenescent phenotype of the FA cells becomes, paradoxically, a driving force to select rare pre-leukemic cells that can overcome the growth-inhibited status characteristic of FA cells: the “dark side” of senescence (Fig. 5)

Summary

Introduction

Cellular senescence is a genetic process allowing proliferation arrest with physiological roles in embryogenesis, the maintenance and regeneration of tissues or the defence mechanism against tumours. ● Stress-induced senescence several other stressful stimuli induce premature senescence again via the activation and permanent maintenance of DDR signalling They constitute a heterogeneous group of events: alterations in DNA methylation and/or histone landscape [19], cell exposure to pro-inflammatory cytokines or the SASP produced by neighbouring cells, oxidative stress or reactive aldehyde due to endogenous cellular metabolism [20], mitochondrial and metabolic dysfunctions [21] (Fig. 1). ● Activation of the p53-p21 and p16-pRb axes Driven by ATM/ATR, DDR signalling leads to cell cycle arrest by activating the p53-p21 and p16-pRb axes, which inhibit factors associated with the G1-S transition Both axes play critical and pleiotropic roles in growth inhibition outcomes: arresting the cell cycle temporarily and permitting DNA damage repair or permanently stopping the cell proliferation of highly damaged cells by inducing senescence or cell death [47].

Helbling-Leclerc et al Traverse fork model

Conclusion

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