A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1

Zheng, X.F. Steven; Acharya, Sanket S.; Choe, Katherine N.; Nikhil, Kumar; Adelmant, Guillaume; Satapathy, Shakti Ranjan; Sharma, Samanta; Viccaro, Keith; Rana, Sandeep; Natarajan, Amarnath; Sicinski, Peter; Marto, Jarrod A.; Shah, Kavita; Chowdhury, Dipanjan

doi:10.1038/s41467-019-12084-x

Cited by 19 publications

(12 citation statements)

References 43 publications

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“…Several modifications of chromatin and of associated proteins that surround DSBs modulate the accessibility of 53BP1 to DNA damage sites. In addition, post-translational modifications of 53BP1 itself tightly control its recruitment to damaged DNA and its subsequent role in DNA damage response (DDR) (18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage

et al. 2021

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Double-strand breaks (DSBs) are harmful lesions and a major cause of genome instability. Studies have suggested a link between the nuclear envelope and the DNA damage response. Here, we show that lamin B1, a major component of the nuclear envelope, interacts directly with 53BP1 protein, which plays a pivotal role in the DSB repair. This interaction is dissociated after DNA damage. Lamin B1 overexpression impedes 53BP1 recruitment to DNA damage sites and leads to a persistence of DNA damage, a defect in nonhomologous end joining and an increased sensitivity to DSBs. The identification of interactions domains between lamin B1 and 53BP1 allows us to demonstrate that the defect of 53BP1 recruitment and the DSB persistence upon lamin B1 overexpression are due to sequestration of 53BP1 by lamin B1. This study highlights lamin B1 as a factor controlling the recruitment of 53BP1 to DNA damage sites upon injury.

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Section: Introductionmentioning

confidence: 99%

Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage

et al. 2021

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“…Moreover, these aberrations were detected upon induction of DSB throughout the cell cycle with mitomycin-C, which may suggest that part of these aberrations may be due to non S-phase damage, maybe during G 1 or G 2 /M. Thus, some studies suggest that PP4 plays a role in the deposition of 53BP1 pathway during mitosis for NHEJ repair in G1, which may support this possibility(52).…”

Section: Discussionmentioning

confidence: 94%

“…This increase may be explained by the fact that SIRT1 and PP4 also induce NHEJ, the less accurate major DSB repair pathway(49,50). Interestingly, although the main role of both PP4 and SIRT1 in DSB repair is through HR, they have been shown to target KAP1 (SIRT1 and PP4) and 53BP1 (PP4) to promote NHEJ activity(49,51,52). However, other evidence suggests that PP4 has an inhibitory effect on the pathway (50) which would fit with NHEJ induction upon SIRT1/PP4 downregulation.…”

Section: Discussionmentioning

confidence: 99%

SIRT1 regulates DNA damage signaling through the PP4 phosphatase complex

Rasti

Becker

Vázquez

et al. 2022

Preprint

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The Sirtuin family of NAD⁺-dependent enzymes plays an important role in maintaining genome stability upon stress. Several mammalian Sirtuins have been linked directly or indirectly to the regulation of DNA damage during replication through Homologous recombination (HR). The role of one of them, SIRT1, is intriguing as it seems to have a general regulatory role in the DNA damage response (DDR) that has not yet been addressed. SIRT1-deficient cells show impaired DDR reflected in a decrease in repair capacity, increased genome instability and decreased levels of γH2AX. Here we unveil a close functional antagonism between SIRT1 and the PP4 phosphatase multiprotein complex in the regulation of the DDR. Upon DNA damage, SIRT1 interacts specifically with the catalytical subunit PP4c and promotes its inhibition by deacetylating the WH1 domain of the regulatory subunits PP4R3α/β. This in turn regulates γH2AX and RPA2 phosphorylation, two key events in the signaling of DNA damage and repair by HR. We propose a mechanism whereby during stress, SIRT1 signaling ensures a global control of DNA damage signaling through PP4.

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“…Protein phosphatase 4 (PP4) dephosphorylates 53BP1 in late mitosis, an event required for 53BP1 recruitment to DSB in G1 phase for NHEJ-mediated repair of DSBs. CDK5 phosphorylates PP4R3β, the PP4 regulatory subunit, which facilitates PP4 action and contributes to cell proliferation-associated NHEJ [170]. However whether this function is active in post-mitotic neurons remains to be determined.…”

Section: Role Of Cdk5 Abnormalities In Ad Via Affecting Dna Damagementioning

confidence: 99%

Contributions of DNA Damage to Alzheimer’s Disease

Lin

Kapoor

et al. 2020

IJMS

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Alzheimer's disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.Int. J. Mol. Sci. 2020, 21, 1666 2 of 26 amyloid (senile) plaques in AD brain [9][10][11]. Furthermore, CDK5 activities affect DNA damage response [12], supporting a linkage of DNA damage with AD [13,14].Aβ peptides are directly produced by sequential cleavages of APP by βand γ-secretase; the proteolytic c-terminal fragment of APP (CTFβ) of β-secretase is cleaved within the cell membrane by γ-secretase to generate neurotoxic Aβ peptides with length ranging from 38-43 residues [15][16][17][18][19]. The 40 residue Aβ peptide (Aβ 1-40 ) is the major product, accounting for more than 50% of Aβ peptides [9,17]. Although the Aβ 1-42 peptide consists of less than 10% of Aβ peptides [16,17], it is more neurotoxic and associates with a higher risk of AD because of its propensity of aggregation [9]. The importance of Aβ in AD pathogenesis is illustrated by mutations of APP, PSEN1, and PREN2 genes in familial AD with the latter two encoding the presenilin 1 and presenilin 2 subunit of γ-secretase. Individuals with these mutations develop early onset dementia in an autosomal-dominant manner [20]; the typical onset starts between 30 and 50 years of age in PSEN1 mutant carriers with some being affected at in their 20s [20,21]. γ-secretase with mutant presenilin 1 or presenilin 2 subunit favors Aβ 1-42 production [16,17]. These genetic observations led to formation of the amyloid cascade hypothesis, in which abnormal Aβ drives AD pathogenesis via regulating other pathological events including tau pathology [22][23][24][25][26][27]. This hypothesis is supported by the similar pathological features between familial AD and sporadic late onset AD (LOAD) [20]. Although familial AD constitutes less than 1% of AD cases [28,29], the hypothesis has been widely accepted to guide research in advancing the understanding of both familial AD and LOAD in the past two decades [30,31].Nonetheless, it is becoming in...

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A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1

Cited by 19 publications

References 43 publications

Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage

Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage

SIRT1 regulates DNA damage signaling through the PP4 phosphatase complex

Contributions of DNA Damage to Alzheimer’s Disease

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