Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair

Lu, Haijun; Shamanna, Raghavendra A.; Freitas, Jessica K. de; Okur, Mustafa Nazir; Khadka, Prabhat; Kulikowicz, Tomasz; Holland, Priscella P.; Tian, Jane; Croteau, Deborah L.; Davis, Anthony J.; Bohr, Vilhelm A.

doi:10.1038/s41467-017-02146-3

Cited by 79 publications

(115 citation statements)

References 67 publications

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ On the other hand, Ku complex is known to interact with RECQL4 and to form a macromolecular assembly promoting NHEJ. A well-known RECQL4-binding partner, namely DDB1 79 , was found to be one of the top 3 master regulators of 3 datasets (SKCM, BLCA and BRCA). DDB1 has been reported to be involved in the damage recognition step of the BER pathway 80 , and to be correlated with a high risk when down-regulated in head and neck squamous cell carcinoma 81 .…”

Section: Discussionmentioning

confidence: 99%

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

Ayyildiz

Antoniali

D’Ambrosio

et al. 2020

Sci Rep

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APE1 is essential in cancer cells due to its central role in the Base Excision Repair pathway of DNA lesions and in the transcriptional regulation of genes involved in tumor progression/chemoresistance. Indeed, APE1 overexpression correlates with chemoresistance in more aggressive cancers, and APE1 protein-protein interactions (PPIs) specifically modulate different protein functions in cancer cells. Although important, a detailed investigation on the nature and function of protein interactors regulating APE1 role in tumor progression and chemoresistance is still lacking. The present work was aimed at analyzing the APE1-PPI network with the goal of defining bad prognosis signatures through systematic bioinformatics analysis. By using a well-characterized HeLa cell model stably expressing a flagged APE1 form, which was subjected to extensive proteomics analyses for immunocaptured complexes from different subcellular compartments, we here demonstrate that APE1 is a central hub connecting different subnetworks largely composed of proteins belonging to cancer-associated communities and/or involved in RNA-and DNA-metabolism. When we performed survival analysis in real cancer datasets, we observed that more than 80% of these APE1-PPI network elements is associated with bad prognosis. Our findings, which are hypothesis generating, strongly support the possibility to infer APE1-interactomic signatures associated with bad prognosis of different cancers; they will be of general interest for the future definition of novel predictive disease biomarkers. Future studies will be needed to assess the function of APE1 in the protein complexes we discovered. Data are available via ProteomeXchange with identifier PXD013368.Alteration of DNA repair mechanisms is an important hallmark of cancer cells, and plays a role both in the onset of an initial cancerous phenotype and in tumor progression. Tumor cells can develop drug resistance through repair mechanisms that counteract the DNA damage induced by chemotherapy or radiotherapy 1,2 . Thus, specific DNA repair inhibitors are often combined with DNA-damaging agents to improve therapy efficacy. Emerging evidences in tumor biology suggest that: i) protein-protein interactions (PPIs) specifically modulate both canonical and non-canonical roles of DNA repair enzymes; ii) RNA processing pathways participate in DNA-Damage Response (DDR); iii) defects in the above-mentioned regulatory mechanisms are associated with cancer genomic instability 3 . Very recent studies clearly show that many DNA repair proteins are associated with those involved in RNA metabolism, proving a role of their interactome network in undertaking non-canonical functions affecting gene expression in tumors. In addition, novel studies have shown that interaction of DDR components and miRNA biogenesis process is linked to cancer development 2 . In the context of these emerging lines, we already demonstrated the crucial role that enzymes belonging to the base excision DNA repair (BER) pathway play 4 . In particular, we showe...

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Section: Discussionmentioning

confidence: 99%

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

Ayyildiz

Antoniali

D’Ambrosio

et al. 2020

Sci Rep

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“…Thus, human premature aging disorders are strongly associated with defects in DSBR, BER, and NER . Furthermore, repair of DNA damage is an energy demanding process and it is becoming increasingly evident that DNA damage and persistent DDR‐linked cellular stress leads to mitochondrial dysfunction and metabolic defects . The following paragraphs discuss the molecular mechanisms underlying this signaling and how it relates to cellular bioenergetics/energy homeostasis and the cellular abundance of ATP and NAD + .…”

Section: Dna Damage Response Pathwaysmentioning

confidence: 99%

“…Thus, human premature aging disorders are strongly associated with defects in DSBR, BER, and NER [14]. Furthermore, repair of DNA damage is an energy demanding process [15][16][17][18][19][20] and it is becoming increasingly evident that DNA damage and persistent DDR-linked cellular stress leads to mitochondrial dysfunction and metabolic defects [21].…”

Section: Dna Damage Response Pathwaysmentioning

confidence: 99%

Toward understanding genomic instability, mitochondrial dysfunction and aging

Fakouri

Demarest

et al. 2018

The FEBS Journal

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The biology of aging is an area of intense research, and many questions remain about how and why cell and organismal functions decline over time. In mammalian cells, genomic instability and mitochondrial dysfunction are thought to be among the primary drivers of cellular aging. This review focuses on the interrelationship between genomic instability and mitochondrial dysfunction in mammalian cells and its relevance to age‐related functional decline at the molecular and cellular level. The importance of oxidative stress and key DNA damage response pathways in cellular aging is discussed, with a special focus on poly (ADP‐ribose) polymerase 1, whose persistent activation depletes cellular energy reserves, leading to mitochondrial dysfunction, loss of energy homeostasis, and altered cellular metabolism. Elucidation of the relationship between genomic instability, mitochondrial dysfunction, and the signaling pathways that connect these pathways/processes are keys to the future of research on human aging. An important component of mitochondrial health preservation is mitophagy, and this and other areas that are particularly ripe for future investigation will be discussed.

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“…The potentially mutagenic impact of resection during G 1 underscores the importance of additional mechanisms to regulate resection (discussed below). Recently, the RECQ family helicase, RECQL4, was identified as a regulator of repair pathway choice between the G 1 and S phase of the cell cycle (17). RECQL4 is recruited to DSBs at all phases of the cell cycle, but it interacts with the NHEJ factors Ku70/80 during G 1 and with MRE11 during S and G 2 .…”

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confidence: 99%

How cells ensure correct repair of DNA double-strand breaks

Her

Bunting

2018

Journal of Biological Chemistry

239

207

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DNA double-strand breaks (DSBs) arise regularly in cells and when left unrepaired cause senescence or cell death. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are the two major DNA-repair pathways. Whereas HR allows faithful DSB repair and healthy cell growth, NHEJ has higher potential to contribute to mutations and malignancy. Many regulatory mechanisms influence which of these two pathways is used in DSB repair. These mechanisms depend on the cell cycle, post-translational modifications, and chromatin effects. Here, we summarize current research into these mechanisms, with a focus on mammalian cells, and also discuss repair by "alternative end-joining" and single-strand annealing.

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Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair

Cited by 79 publications

References 67 publications

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

Toward understanding genomic instability, mitochondrial dysfunction and aging

How cells ensure correct repair of DNA double-strand breaks

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