DNA-dependent Protein Kinase Regulates DNA End Resection in Concert with Mre11-Rad50-Nbs1 (MRN) and Ataxia Telangiectasia-mutated (ATM)

Zhou, Yi; Paull, Tanya T.

doi:10.1074/jbc.m113.514398

Cited by 61 publications

(62 citation statements)

References 59 publications

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“…Given that cells unable to phosphorylate the ABCDE sites remove cisplatin from their DNA at a lower rate than cells with or without wild-type DNA-PKcs, it seems likely that ABCDE phosphorylation is required to disengage DNA-PK (and attempted NHEJ) from those DNA ends. Consistent with this interpretation, during revision of the manuscript, Zhou and Paull reported that DNA-PK and MRN (Mre11-Rad50-Nbs1) regulate end resection and that ABCDE phosphorylation was crucial for promoting end resection (48). Understanding how DNA-PK disengages from these ends is an important, outstanding question.…”

Section: Discussionmentioning

confidence: 81%

Unraveling the Complexities of DNA-Dependent Protein Kinase Autophosphorylation

Neal

Sugiman-Marangos

VanderVere-Carozza

et al. 2014

Molecular and Cellular Biology

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f DNA-dependent protein kinase (DNA-PK) orchestrates DNA repair by regulating access to breaks through autophosphorylations within two clusters of sites (ABCDE and PQR). Blocking ABCDE phosphorylation (by alanine mutation) imparts a dominant negative effect, rendering cells hypersensitive to agents that cause DNA double-strand breaks. Here, a mutational approach is used to address the mechanistic basis of this dominant negative effect. Blocking ABCDE phosphorylation hypersensitizes cells to most types of DNA damage (base damage, cross-links, breaks, and damage induced by replication stress), suggesting that DNA-PK binds DNA ends that result from many DNA lesions and that blocking ABCDE phosphorylation sequesters these DNA ends from other repair pathways. This dominant negative effect requires DNA-PK's catalytic activity, as well as phosphorylation of multiple (non-ABCDE) DNA-PK catalytic subunit (DNA-PKcs) sites. PSIPRED analysis indicates that the ABCDE sites are located in the only contiguous extended region of this huge protein that is predicted to be disordered, suggesting a regulatory role(s) and perhaps explaining the large impact ABCDE phosphorylation has on the enzyme's function. Moreover, additional sites in this disordered region contribute to the ABCDE cluster. These data, coupled with recent structural data, suggest a model whereby early phosphorylations promote initiation of nonhomologous end joining (NHEJ), whereas ABCDE phosphorylations, potentially located in a "hinge" region between the two domains, lead to regulated conformational changes that initially promote NHEJ and eventually disengage NHEJ.

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Section: Discussionmentioning

confidence: 81%

Unraveling the Complexities of DNA-Dependent Protein Kinase Autophosphorylation

Neal

Sugiman-Marangos

VanderVere-Carozza

et al. 2014

Molecular and Cellular Biology

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“…Competition occurs during G2 phase when both of the repair choices are present. As reported, the MRN complex can promote DNA-PKcs auto-phosphorylation [36], which is associated with dissociation of DNA-PKcs from the DSBs [37] and the assembly of an HR-associated nuclease (such as Exo1) at the DSBs [36], leading to DSB resection and HR repair progression. Notably, these findings also suggest that the auto-phosphorylation of DNA-PKcs abrogates the NHEJ-associated role of DNA-PKcs, whereas the trans-phosphorylation of DNA-PKcs facilitates this role and somehow directs the choice between NHEJ and HR.…”

Section: Dsb Resection Directs Competition Between Hr and Nhejmentioning

confidence: 73%

“…Thus, DNA-PKcs might function as the molecular switch that coordinates end processing and end ligation at the DNA ends through its differential phosphorylation status [35]. Another study indicated that DNA-PKcs auto-phosphorylation represented the inactive DNA-PKcs status and was associated with the dissociation of DNA-PKcs from DSBs [36,37], suggesting that the auto-phosphorylation of DNA-PKcs results in inactivation, whereas the trans-phosphorylation of DNA-PKcs facilitates its NHEJ-associated roles.…”

Section: The Processing Of Dsb Dna Endmentioning

confidence: 99%

Non-homologous end joining: advances and frontiers

Yang

Guo

2016

ABBS

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DNA double-strand breaks (DSBs) are the most serious form of DNA damage. In human cells, non-homologous end joining (NHEJ) is the major pathway for the repair of DSBs. Different types of DSBs result in different subsets of NHEJ repair strategies. These variations in NHEJ repair strategies depend on numerous elements, such as the flexible recruitment of NHEJ-related proteins, the complexity of the DSB ends, and the spatial-and temporal-ordered formation of the multiprotein complex. On the one hand, current studies of DNA DSBs repair focus on the repair pathway choices between homologous recombination and classic or alternative NHEJ. On the other hand, increasing researches have also deepened the significance and dug into the cross-links between the NHEJ pathway and the area of genome organization and aging. Although remarkable progress has been made in elucidating the underlying principles during the past decades, the detailed mechanism of action in response to different types of DSBs remains largely unknown and needs further evaluation in the future study.

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“…Thus, suppression occurs when the Ku-imposed block of Exo1 is relieved, but not because NHEJ is inhibited (22). Finally, Ku binding to DSB ends has been shown to block Exo1 access in vitro (23,24).…”

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confidence: 99%

Interplay between Ku and Replication Protein A in the Restriction of Exo1-mediated DNA Break End Resection

Krasner

Daley

Sung

et al. 2015

Journal of Biological Chemistry

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Background: DNA end resection is the first step in DNA double-strand break repair by homologous recombination. Results: Ku and RPA compete for binding to ends with ssDNA. Ku blocks resection by Exo1, whereas RPA allows resection to proceed. Conclusion: Longer ssDNA overhangs favor RPA binding and further resection. Significance: Interplay between Ku and RPA binding to DNA ends may affect DNA repair pathway choice.

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DNA-dependent Protein Kinase Regulates DNA End Resection in Concert with Mre11-Rad50-Nbs1 (MRN) and Ataxia Telangiectasia-mutated (ATM)

Cited by 61 publications

References 59 publications

Unraveling the Complexities of DNA-Dependent Protein Kinase Autophosphorylation

Unraveling the Complexities of DNA-Dependent Protein Kinase Autophosphorylation

Non-homologous end joining: advances and frontiers

Interplay between Ku and Replication Protein A in the Restriction of Exo1-mediated DNA Break End Resection

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