RESEARCH:
Transcription Stress & Genome stability:
The Marteijn lab studies the severe effects of DNA damage on transcription including its physiological consequences like aging. Cells rely on RNA polymerase II (Pol II)-mediated transcription to accurately transcribe their genomes, ensuring proper gene expression and correct cellular function. However, the DNA template that is transcribed by Pol II is continuously challenged by DNA damage, which stall Pol II and disrupt the production of essential RNA molecules. If not properly resolved, these Transcription-blocking DNA lesions (TBLs) result in transcription stress and cellular dysfunction, ultimately leading to neurodegeneration, and premature aging. Specialized transcription-coupled repair (TCR) pathways have evolved that remove TBLs to preserve transcriptional integrity, an essential process underscored by the severe premature aging and developmental and neurological defects observed in patients with inherited TCR deficiencies.
Our lab studies the molecular mechanisms that govern cellular responses to transcription stress and TCR, to uncover how transcription-blocking DNA lesions drive aging and disease. By combining advanced live-cell imaging with state-of-the-art multi-omics approaches, we investigate how cells sense and remove DNA lesions that obstruct transcription, how cells cope with transcription stress and how failures in these pathways contribute to disorders such as Cockayne Syndrome and neurodegeneration.
Over the years, using CRISPR/Cas9 genomic screens and proteomics, we identified several core factors of the transcription-coupled nucleotide excision repair (TC-NER) pathway, including UVSSA, STK19, ELOF1, and HLTF, and demonstrated their molecular mechanisms, shaping the current understanding of TC-NER. Our work also revealed that damage-stalled Pol II is the primary driver of Cockayne Syndrome pathology, providing a unifying explanation for the disease’s severe clinical features. Beyond TC-NER, our lab recently discovered a new transcription-coupled repair pathway dedicated to removing DNA-protein crosslinks (DPCs). We elucidated its mechanism, showed that it acts independently of TC-NER, and linked transcription-blocking DPCs directly to neurodegeneration. Moreover, we discovered of transcriptional responses upon DNA damage involving the spliceosome and R-loops, damage-induced histone exchange, and degradation of promoter-paused Pol II. To enable these discoveries, we developed multiple single-cell tools for sensitively quantifying TCR activity and transcription stress responses in living cells.
Selected publications of the Marteijn lab:
- van Sluis, M., Gonzalo-Hansen, C., Li, Q., Lans, H., Wang, D. and Marteijn, J.A.
Mechanisms of transcription-coupled repair and DNA damage surveillance in health and disease.
Nat Rev Mol Cell Biol (2025). 10.1038/s41580-025-00915-3 - van Sluis, M., Yu, Q., van der Woude, M., Gonzalo-Hansen, C., Dealy, S.C., Janssens, R.C., Somsen, H.B., Ramadhin, A.R., Dekkers, D.H.W., Wienecke, H.L., et al. and Marteijn, J.A.
Transcription-coupled DNA-protein crosslink repair by CSB and CRL4(CSA)-mediated degradation.
Nat Cell Biol 26, 770–783 (2024). 10.1038/s41556-024-01394-y - Ramadhin, A.R., Lee, S.H., Zhou, D., Salmazo, A., Gonzalo-Hansen, C., van Sluis, M., Blom, C.M.A., Janssens, R.C., Raams, A., Dekkers, D., et al. and Marteijn, J.A.
STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment.
Mol Cell 84, 4740–4757.e4712 (2024). 10.1016/j.molcel.2024.10.030 - van Toorn, M., Turkyilmaz, Y., Han, S., Zhou, D., Kim, H.S., Salas-Armenteros, I., Kim, M., Akita, M., Wienholz, F., Raams, A., et al. and Marteijn, J.A.
Active DNA damage eviction by HLTF stimulates nucleotide excision repair.
Mol Cell 82, 1343–1358.e1348 (2022). 10.1016/j.molcel.2022.02.020 - Steurer, B., Janssens, R.C., Geijer, M.E., Aprile-Garcia, F., Geverts, B., Theil, A.F., Hummel, B., van Royen, M.E., Evers, B., Bernards, R., et al. and Marteijn, J.A.
DNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound Pol II.
Nat Commun 13, 3624 (2022). 10.1038/s41467-022-31329-w - Geijer, M.E., Zhou, D., Selvam, K., Steurer, B., Mukherjee, C., Evers, B., Cugusi, S., van Toorn, M., van der Woude, M., Janssens, R.C., et al. and Marteijn, J.A.
Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability.
Nat Cell Biol 23, 608–619 (2021). 10.1038/s41556-021-00692-z - Lans, H., Hoeijmakers, J.H.J., Vermeulen, W. and Marteijn, J.A.
The DNA damage response to transcription stress.
Nat Rev Mol Cell Biol 20, 766–784 (2019). 10.1038/s41580-019-0169-4 - Tresini, M., Warmerdam, D.O., Kolovos, P., Snijder, L., Vrouwe, M.G., Demmers, J.A., van I.W.F., Grosveld, F.G., Medema, R.H., Hoeijmakers, J.H., Mullenders, L.H., Vermeulen, W. and Marteijn, J.A.
The core spliceosome as target and effector of non-canonical ATM signalling.
Nature 523, 53–58 (2015). 10.1038/nature14512 - Schwertman, P., Lagarou, A., Dekkers, D.H., Raams, A., van der Hoek, A.C., Laffeber, C., Hoeijmakers, J.H., Demmers, J.A., Fousteri, M., Vermeulen, W. and Marteijn, J.A.
UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair.
Nat Genet 44, 598–602 (2012). 10.1038/ng.2230
