Ubiquitylation of MYC couples transcription elongation with double-strand break repair at active promoters

Endres, Theresa; Solvie, Daniel; Heidelberger, Jan B.; Andrioletti, Valentina; Baluapuri, Apoorva; Ade, Carsten P.; Muhar, Matthias; Eilers, Ursula; Vos, Seychelle M.; Cramer, Patrick; Zuber, Johannes; Beli, Petra; Popov, Nikita; Wolf, Elmar; Gallant, Peter; Eilers, Martin

doi:10.1016/j.molcel.2020.12.035

Cited by 31 publications

(31 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Currently, there are several models demonstrating the different modes of MYC transactivation function, including specific-gene regulation, global gene activation, and gene-specific affinity models (1,3). New studies also suggest that MYC supports genome integrity by clearing stalled RNAPII and resolving transcriptionreplication conflicts (1,16).…”

Section: Introductionmentioning

confidence: 99%

Targeting the MYC Ubiquitination-Proteasome Degradation Pathway for Cancer Therapy

Sun

Sears

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

Deregulated MYC overexpression and activation contributes to tumor growth and progression. Given the short half-life and unstable nature of the MYC protein, it is not surprising that the oncoprotein is highly regulated via diverse posttranslational mechanisms. Among them, ubiquitination dynamically controls the levels and activity of MYC during normal cell growth and homeostasis, whereas the disturbance of the ubiquitination/deubiquitination balance enables unwanted MYC stabilization and activation. In addition, MYC is also regulated by SUMOylation which crosstalks with the ubiquitination pathway and controls MYC protein stability and activity. In this mini-review, we will summarize current updates regarding MYC ubiquitination and provide perspectives about these MYC regulators as potential therapeutic targets in cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

Targeting the MYC Ubiquitination-Proteasome Degradation Pathway for Cancer Therapy

Sun

Sears

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…For example, Chd1 may also interact with PARP1 and the histone acetyltransferase Tip60, and both histone ADP ribosylation and acetylation are involved in chromatin relaxation at DNA repair sites 30 , 31 . Other major transcriptional regulators such as Myc and Paf1c mediate repair of transcription-associated DNA breaks through H2B ubiquitination 32 , which may be a mechanism shared by Chd1, as global H2Bub reduction was observed in Chd1 KO cells 33 . Further biochemical studies of how the activity of Atm and other aspects of DNA repair are modulated by Chd1 will shed light on the mechanisms by which stem and progenitor cells can undergo hypertranscription while preserving DNA integrity.…”

Section: Discussionmentioning

confidence: 99%

Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells

Bulut-Karslıoğlu

Kim

et al. 2021

Nat Commun

View full text Add to dashboard Cite

Stem and progenitor cells undergo a global elevation of nascent transcription, or hypertranscription, during key developmental transitions involving rapid cell proliferation. The chromatin remodeler Chd1 mediates hypertranscription in pluripotent cells but its mechanism of action remains poorly understood. Here we report a novel role for Chd1 in protecting genome integrity at promoter regions by preventing DNA double-stranded break (DSB) accumulation in ES cells. Chd1 interacts with several DNA repair factors including Atm, Parp1, Kap1 and Topoisomerase 2β and its absence leads to an accumulation of DSBs at Chd1-bound Pol II-transcribed genes and rDNA. Genes prone to DNA breaks in Chd1 KO ES cells are longer genes with GC-rich promoters, a more labile nucleosomal structure and roles in chromatin regulation, transcription and signaling. These results reveal a vulnerability of hypertranscribing stem cells to accumulation of endogenous DNA breaks, with important implications for developmental and cancer biology.

show abstract

“…The transition from initiating to elongating RNA pol II (promoter release) requires also the MYC-dependent recruitment of the PAF1c complex and the ubiquitin-mediated turnover of promoter-associated MYC, which favors the transfer of PAF1c from MYC to RNA pol II, thus triggering promoter escape and processive elongation [26]. Since loss of PAF1c, while altering RNA pol II dynamics, has a limited impact on transcription, it is possible that this molecular circuit might be required to mitigate or repress intrinsic transcriptional stress [26].…”

Section: Transcriptional Repression By Mycmentioning

confidence: 99%

“…Coherently, MYC silencing leads to the decrease in ATM and DNA-PKcs, which, in turn, results in reduced DSB repair [90]. More recently, proper turnover of promoters' bound MYC was shown to be required for the efficient repair of TSS-associated DSBs [26].…”

Section: Replicative Stress Is a Therapeutic Target For Myc-driven Cancersmentioning

confidence: 99%

MYC-Induced Replicative Stress: A Double-Edged Sword for Cancer Development and Treatment

Curti

Campaner

2021

IJMS

View full text Add to dashboard Cite

MYC is a transcription factor that controls the expression of a large fraction of cellular genes linked to cell cycle progression, metabolism and differentiation. MYC deregulation in tumors leads to its pervasive genome-wide binding of both promoters and distal regulatory regions, associated with selective transcriptional control of a large fraction of cellular genes. This pairs with alterations of cell cycle control which drive anticipated S-phase entry and reshape the DNA-replication landscape. Under these circumstances, the fine tuning of DNA replication and transcription becomes critical and may pose an intrinsic liability in MYC-overexpressing cancer cells. Here, we will review the current understanding of how MYC controls DNA and RNA synthesis, discuss evidence of replicative and transcriptional stress induced by MYC and summarize preclinical data supporting the therapeutic potential of triggering replicative stress in MYC-driven tumors.

show abstract

Ubiquitylation of MYC couples transcription elongation with double-strand break repair at active promoters

Cited by 31 publications

References 106 publications

Targeting the MYC Ubiquitination-Proteasome Degradation Pathway for Cancer Therapy

Targeting the MYC Ubiquitination-Proteasome Degradation Pathway for Cancer Therapy

Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells

MYC-Induced Replicative Stress: A Double-Edged Sword for Cancer Development and Treatment

Contact Info

Product

Resources

About