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ATM controls DNA repair and mitochondria transfer between neighboring cells.

ABSTRACT: Intercellular communication is essential for multicellular tissue vitality and homeostasis. We show that healthy cells message protective signals through direct cell-cell connections to adjacent DNA-damaged cells in a microtubule-dependent manner. In DNA-damaged cells, mitochondria restoration is facilitated by fusion with undamaged mitochondria from healthy cells and their DNA damage repair is optimized in presence of healthy cells. Both, mitochondria transfer and intercellular signaling for an enhanced DNA damage response are critically regulated by the activity of the DNA repair protein ataxia telangiectasia mutated (ATM). These healthy-to-damaged prosurvival processes sustain normal tissue integrity and may be exploitable for overcoming resistance to therapy in diseases such as cancer.

SUBMITTER: Jin S

PROVIDER: S-EPMC6842230 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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ATM controls DNA repair and mitochondria transfer between neighboring cells.

Jin Sha S Cordes Nils N

Cell communication and signaling : CCS 20191108 1

Intercellular communication is essential for multicellular tissue vitality and homeostasis. We show that healthy cells message protective signals through direct cell-cell connections to adjacent DNA-damaged cells in a microtubule-dependent manner. In DNA-damaged cells, mitochondria restoration is facilitated by fusion with undamaged mitochondria from healthy cells and their DNA damage repair is optimized in presence of healthy cells. Both, mitochondria transfer and intercellular signaling for an ...[more]

PMID: 31703695

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Project description: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.

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