ID3 regulates the MDC1-mediated DNA damage response in order to maintain genome stability

Lee, Jung-Hee; Park, Seon-Joo; Hariharasudhan, Gurusamy; Kim, Minji; Jung, Soon‐Moon; Jeong, Seo-Yeon; Chang, In Youb; Kim, Cheol-Hee; Kim, Eunae; Yu, Jong Pil; Bae, Sangsu; You, Ho Jin

doi:10.1038/s41467-017-01051-z

Cited by 26 publications

(40 citation statements)

References 60 publications

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“…In response to double-stranded breaks, ID3 is phosphorylated by ATM. Phosphorylated ID3 accumulates at damage sites and promotes binding of MDC1 to ␥H2AX through interacting with both MDC1 and ␥H2AX (38). In this study, we found that RPL6 also accumulates at damage sites and is essential for interaction between MDC1 and ␥H2AX.…”

Section: Discussionsupporting

confidence: 53%

Ribosomal protein L6 (RPL6) is recruited to DNA damage sites in a poly(ADP-ribose) polymerase–dependent manner and regulates the DNA damage response

Yang

Zang

et al. 2019

Journal of Biological Chemistry

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Edited by Patrick SungRibosomal proteins are the building blocks of ribosome biogenesis. Beyond their known participation in ribosome assembly, the ribosome-independent functions of ribosomal proteins are largely unknown. Here, using immunoprecipitation, subcellular fractionation, His-ubiquitin pulldown, and immunofluorescence microscopy assays, along with siRNA-based knockdown approaches, we demonstrate that ribosomal protein L6 (RPL6) directly interacts with histone H2A and is involved in the DNA damage response (DDR). We found that in response to DNA damage, RPL6 is recruited to DNA damage sites in a poly-(ADP-ribose) polymerase (PARP)-dependent manner, promoting its interaction with H2A. We also observed that RPL6 depletion attenuates the interaction between mediator of DNA damage checkpoint 1 (MDC1) and H2A histone family member X, phosphorylated (␥H2AX), impairs the accumulation of MDC1 at DNA damage sites, and reduces both the recruitment of ring finger protein 168 (RNF168) and H2A Lys-15 ubiquitination (H2AK15ub). These RPL6 depletion-induced events subsequently inhibited the recruitment of the following downstream repair proteins: tumor protein P53-binding protein 1 (TP53BP1) and BRCA1, DNA repair-associated (BRCA1). Moreover, the RPL6 knockdown resulted in defects in the DNA damage-induced G 2 -M checkpoint, DNA damage repair, and cell survival. In conclusion, our study identifies RPL6 as a critical regulatory factor involved in the DDR. These findings expand our knowledge of the extraribosomal functions of ribosomal proteins in cell physiology and deepen our understanding of the molecular mechanisms underlying DDR regulation. 3 The abbreviations used are: DSB, double-stranded break; DDR, DNA damage response; PARP, poly(ADP-ribose) polymerase; MDC1, mediator of DNA damage checkpoint 1; ␥H2AX, H2A histone family member X; NHEJ, nonhomologous end joining; HR, homologous recombination; IP, immunoprecipitation.

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Section: Discussionsupporting

confidence: 53%

Ribosomal protein L6 (RPL6) is recruited to DNA damage sites in a poly(ADP-ribose) polymerase–dependent manner and regulates the DNA damage response

Yang

Zang

et al. 2019

Journal of Biological Chemistry

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“…These data suggest a model in which ID4 associates with the DNA damage repair apparatus at sites of genome instability or damage via its interaction with MDC1. MDC1 was also recently found to associate with ID3, suggesting that this is a conserved feature of ID proteins (74). How MDC1 binds ID4 is unknown, however a quasi HLH domain (75) structure within MDC1 may enable interaction with the HLH domain of ID4.…”

Section: Discussionmentioning

confidence: 99%

Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer

Baker

Holliday

Roden

et al. 2020

Preprint

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Background Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of Differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC, through unknown mechanisms. Methods Here, we have defined unique molecular insights into the function of ID4 in BLBC and the related disease high-grade serous ovarian cancer (HGSOC), by combining RIME proteomic analysis, ChIP-seq mapping of genomic binding sites and RNA-seq. Results These studies reveal novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage. Analysis of clinical samples demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1 -mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair deficiency. Conclusions These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOC.

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“…Deficiency in MDC1, much like BRCA1, results in hypersensitivity to double-stranded DNA breaks (Ando et al, 2013, Lou et al, 2006). MDC1 was also recently found to associate with ID3, suggesting that this is a conserved feature of ID proteins (Lee et al, 2017). MDC1 also interacted with many of the sites of chromatin interaction by ID4, and this was increased following DNA damage.…”

Section: Discussionmentioning

confidence: 96%

A novel role for the HLH protein Inhibitor of Differentiation 4 (ID4) in the DNA damage response in basal-like breast cancer

Roden

Holliday

et al. 2018

Preprint

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Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of Differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC, through unknown mechanisms. Here, we have defined a molecular mechanism of action for ID4 in BLBC and the related disease highgrade serous ovarian cancer (HGSOV), by combining RIME proteomic analysis and ChIP-Seq mapping of genomic binding sites. Remarkably, these studies have revealed novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage and regulating DNA damage signalling. Clinical analysis demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair pathways. These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOV.

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ID3 regulates the MDC1-mediated DNA damage response in order to maintain genome stability

Cited by 26 publications

References 60 publications

Ribosomal protein L6 (RPL6) is recruited to DNA damage sites in a poly(ADP-ribose) polymerase–dependent manner and regulates the DNA damage response

Ribosomal protein L6 (RPL6) is recruited to DNA damage sites in a poly(ADP-ribose) polymerase–dependent manner and regulates the DNA damage response

Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer

A novel role for the HLH protein Inhibitor of Differentiation 4 (ID4) in the DNA damage response in basal-like breast cancer

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