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Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration
Published on: December 27, 2024
Modulation of proteostasis counteracts oxidative stress and affects DNA base excision repair capacity in
Mattia Poletto1, Di Yang1, Sally C Fletcher1
1CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, Oxford OX37DQ, UK.
Abstract:
Ataxia telangiectasia (A-T) is a syndrome associated with loss of ATM protein function. Neurodegeneration and cancer predisposition, both hallmarks of A-T, are likely to emerge as a consequence of the persistent oxidative stress and DNA damage observed in this disease. Surprisingly however, despite these severe features, a lack of functional ATM is still compatible with early life, suggesting that adaptation mechanisms contributing to cell survival must be in place. Here we address this gap in our knowledge by analysing the process of human fibroblast adaptation to the lack of ATM. We identify profound rearrangement in cellular proteostasis occurring very early on after loss of ATM in order to counter protein damage originating from oxidative stress. Change in proteostasis, however, is not without repercussions. Modulating protein turnover in ATM-depleted cells also has an adverse effect on the DNA base excision repair pathway, the major DNA repair system that deals with oxidative DNA damage. As a consequence, the burden of unrepaired endogenous DNA lesions intensifies, progressively leading to genomic instability. Our study provides a glimpse at the cellular consequences of loss of ATM and highlights a previously overlooked role for proteostasis in maintaining cell survival in the absence of ATM function.
Insights
Ataxia telangiectasia (A-T) adaptation involves early proteostasis changes to manage oxidative stress. However, this impacts DNA repair, leading to genomic instability in ATM-deficient cells.
Area of Science:
- Cellular Biology
- Genetics
- Molecular Biology
Background:
- Ataxia telangiectasia (A-T) is characterized by ATM protein loss, leading to neurodegeneration and cancer.
- Persistent oxidative stress and DNA damage are hallmarks of A-T, yet cells can survive early life, indicating adaptation mechanisms.
- The cellular response to ATM deficiency remains incompletely understood.
Purpose of the Study:
- To investigate human fibroblast adaptation to the absence of ATM protein.
- To identify early cellular changes that facilitate survival despite ATM loss.
- To understand the consequences of ATM deficiency on cellular proteostasis and DNA repair.
Main Methods:
- Analysis of human fibroblasts lacking functional ATM protein.
- Assessment of proteostasis rearrangements in response to ATM loss.
- Evaluation of the impact of altered proteostasis on DNA base excision repair pathways.
Main Results:
- Loss of ATM function triggers significant early rearrangements in cellular proteostasis to combat oxidative stress-induced protein damage.
- Altered proteostasis in ATM-deficient cells adversely affects the DNA base excision repair pathway.
- This disruption leads to an accumulation of unrepaired DNA lesions and subsequent genomic instability.
Conclusions:
- Cellular adaptation to ATM loss involves early proteostasis modulation.
- ATM deficiency compromises DNA repair mechanisms through proteostasis alterations.
- Proteostasis plays a critical, previously unrecognized role in cell survival in the absence of ATM function, despite leading to genomic instability.
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