ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation

Weegen, van der; Lint, de; Heuvel, Sander van den; Nakazawa,; Narayanan,; Klaassen,; Wondergem,; Roohollahi,; Schie, Loes van; Hara,; Ljungman,; Ogi,; Wolthuis,; Luijsterburg,

doi:10.1101/2021.02.25.432427

Cited by 2 publications

(1 citation statement)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The whole-genome CRISPR screen for VU1365-T has been performed essentially, as previously described with a few modifications 48 . In brief, three populations of VU1365-T cells were transduced with a TKOV3 library at an infection rate of ~ 0.2 .…”

Section: Methodsmentioning

confidence: 99%

BIRC2–BIRC3 amplification: a potentially druggable feature of a subset of head and neck cancers in patients with Fanconi anemia

Roohollahi

Jong

Pai

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

Head-and-neck squamous cell carcinomas (HNSCCs) are relatively common in patients with Fanconi anemia (FA), a hereditary chromosomal instability disorder. Standard chemo-radiation therapy is not tolerated in FA due to an overall somatic hypersensitivity to such treatment. The question is how to find a suitable alternative treatment. We used whole-exome and whole genome mRNA sequencing to identify major genomic and transcriptomic events associated with FA-HNSCC. CRISPR-engineered FA-knockout models were used to validate a number of top hits that were likely to be druggable. We identified deletion of 18q21.2 and amplification of 11q22.2 as prevailing copy-number alterations in FA HNSCCs, the latter of which was associated with strong overexpression of the cancer-related genes YAP1, BIRC2, BIRC3 (at 11q22.1-2). We then found the drug AZD5582, a known small molecule inhibitor of BIRC2-3, to selectively kill FA tumor cells that overexpressed BIRC2-3. This occurred at drug concentrations that did not affect the viability of untransformed FA cells. Our data indicate that 11q22.2 amplifications are relatively common oncogenic events in FA-HNSCCs, as holds for non FA-HNSCC. Therefore, chemotherapeutic inhibition of overexpressed BIRC2-3 may provide the basis for an approach to develop a clinically realistic treatment of FA-HNSCCs that carry 11q22.2 amplifications.

show abstract

Section: Methodsmentioning

confidence: 99%

BIRC2–BIRC3 amplification: a potentially druggable feature of a subset of head and neck cancers in patients with Fanconi anemia

Roohollahi

Jong

Pai

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability

et al. 2021

View full text Add to dashboard Cite

Correct transcription is crucial for life. However, DNA damage severely impedes elongating RNA Polymerase II (Pol II), causing transcription inhibition and transcription-replication conflicts. Cells are equipped with intricate mechanisms to counteract the severe consequence of these transcription-blocking lesions (TBLs). However, the exact mechanism and factors involved remain largely unknown. Here, using a genome-wide CRISPR/cas9 screen, we identified elongation factor ELOF1 as an important factor in the transcription stress response upon DNA damage. We show that ELOF1 has an evolutionary conserved role in Transcription-Coupled Nucleotide Excision Repair (TC-NER), where it promotes recruitment of the TC-NER factors UVSSA and TFIIH to efficiently repair TBLs and resume transcription. Additionally, ELOF1 modulates transcription to protect cells from transcription-mediated replication stress, thereby preserving genome stability. Thus, ELOF1 protects the transcription machinery from DNA damage via two distinct mechanisms.

show abstract

ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation

Cited by 2 publications

References 38 publications

BIRC2–BIRC3 amplification: a potentially druggable feature of a subset of head and neck cancers in patients with Fanconi anemia

BIRC2–BIRC3 amplification: a potentially druggable feature of a subset of head and neck cancers in patients with Fanconi anemia

Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability

Contact Info

Product

Resources

About