Lack of DNA polymerase μ affects the kinetics of DNA double-strand break repair and impacts on cellular senescence

Chayot, Romain; Danckært, Anne; Montagne, Benjamin; Ricchetti, Miria

doi:10.1016/j.dnarep.2010.09.001

Cited by 22 publications

(18 citation statements)

References 40 publications

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“…Polm null bone marrow cells irradiated in vivo show defective DSB repair and sensitivity for IR-induced chromosomal aberrations [813]. Polm null MEFs have defective kinetics of IRinduced DSB repair measured by gH2AX foci and consequently have an exaggerated Chk2 T68 phosphorylation checkpoint response [814]. These mutant cells also show more pronounced senescence [814].…”

Section: Polymerases L and Mmentioning

confidence: 97%

See 1 more Smart Citation

Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography

Thompson

2012

Mutation Research/Reviews in Mutation Research

328

283

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Section: Polymerases L and Mmentioning

confidence: 97%

“…Polm null MEFs have defective kinetics of IRinduced DSB repair measured by gH2AX foci and consequently have an exaggerated Chk2 T68 phosphorylation checkpoint response [814]. These mutant cells also show more pronounced senescence [814].…”

Section: Polymerases L and Mmentioning

confidence: 98%

Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography

Thompson

2012

Mutation Research/Reviews in Mutation Research

328

283

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“…Transgenic animals deficient in Pol μ expression exhibit impaired immunoglobulin κ light chain rearrangement, leading to reduced levels of mature B-cells 9,12 . In a similar fashion, Pol μ aids in repair of DJ H rearrangements during embryonic development 11 and is involved in repair of DNA breaks due to ionizing radiation 12,13 .…”

mentioning

confidence: 98%

Sustained active site rigidity during synthesis by human DNA polymerase μ

Moon

Pryor

Ramsden

et al. 2014

Nat Struct Mol Biol

128

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DNA polymerase mu (Pol μ) is the only template-dependent human DNA polymerase capable of repairing double strand DNA breaks (DSBs) with unpaired 3′-ends in non-homologous end joining (NHEJ). To probe this function, we structurally characterized Pol μ’s catalytic cycle for single nucleotide incorporation. These structures indicate that, unlike other template-dependent DNA polymerases, there are no large-scale conformational changes in protein subdomains, amino acid side chains, or DNA upon dNTP binding or catalysis. Instead, the only major conformational change is seen earlier in the catalytic cycle, when the flexible Loop1 region repositions upon DNA binding. Pol μ variants with changes in Loop1 have altered catalytic properties and are partially defective in NHEJ. The results indicate that specific Loop1 residues contribute to Pol μ’s unique ability to catalyze template-dependent NHEJ of DSBs with unpaired 3′-ends.

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“…For example, resistance to ionizing radiation, a hallmark of proficiency in NHEJ, is not affected by deficiency in Pol λ (16,17), whereas the effects of deficiency in Pol μ on resistance to ionizing radiation depends partly on cell type (16,18,19). Effects of these polymerases on the fidelity of NHEJ have also been observed (9,10,16,(20)(21)(22)(23), although interpretations vary as to whether differences in catalytic activities are important (i.e., they are redundant), or even if their catalytic activities are relevant at all.…”

mentioning

confidence: 99%

Essential role for polymerase specialization in cellular nonhomologous end joining

Pryor

Waters

Aza

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Nonhomologous end joining (NHEJ) repairs chromosome breaks and must remain effective in the face of extensive diversity in broken end structures. We show here that this flexibility is often reliant on the ability to direct DNA synthesis across strand breaks, and that polymerase (Pol) μ and Pol λ are the only mammalian DNA polymerases that have this activity. By systematically varying substrate in cells, we show each polymerase is uniquely proficient in different contexts. The templating nucleotide is also selected differently, with Pol μ using the unpaired base adjacent to the downstream 5′ phosphate even when there are available template sites further upstream of this position; this makes Pol μ more flexible but also less accurate than Pol λ. Loss of either polymerase alone consequently has clear and distinguishable effects on the fidelity of repair, but end remodeling by cellular nucleases and the remaining polymerase helps mitigate the effects on overall repair efficiency. Accordingly, when cells are deficient in both polymerases there is synergistic impact on NHEJ efficiency, both in terms of repair of defined substrates and cellular resistance to ionizing radiation. Pol μ and Pol λ thus provide distinct solutions to a problem for DNA synthesis that is unique to this pathway and play a key role in conferring on NHEJ the flexibility required for accurate and efficient repair.nonhomologous end joining | double-strand break repair | Pol X | polymerase mu | polymerase lambda

show abstract

Lack of DNA polymerase μ affects the kinetics of DNA double-strand break repair and impacts on cellular senescence

Cited by 22 publications

References 40 publications

Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography

Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography

Sustained active site rigidity during synthesis by human DNA polymerase μ

Essential role for polymerase specialization in cellular nonhomologous end joining

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