10 June 2021

Dear world: meet ELOF1 – the newly discovered core factor in the TC-NER pathway

Bianca-Olivia Nita

Bianca-Olivia Nita

Damaged DNA is a problem for cells. DNA replication and transcription are hampered if the DNA template is damaged. Moreover, accumulating DNA damage is one of the hallmarks of cancer. Luckily our cells are equipped with machineries to fix damaged DNA. One of those is the transcription-coupled nucleotide excision repair (TC-NER) pathway, which removes UV induced damage. Until now, we only knew three core factors that could recognize DNA damage-stalled RNA polymerase: CSA, CSB and UVSSA. Using CRISPR/Cas9 technology Oncode Investigator Jurgen Marteijn’s new research has identified a fourth core factor, called ELOF1. The results of this research are now published in Nature Cell Biology.

DNA damage can be removed when it blocks the transcription machinery, which transcribes DNA into RNA. ‘We refer to that pathway as transcription-coupled nucleotide excision repair (TC-NER)’, says Marteijn. ‘We basically knew three core factors that recognize that the RNA polymerase is blocked at sites of DNA damage: CSA, CSB, and UVSSA, of which the latter was discovered in my lab back in 2012. And now we added ELOF1 as the fourth factor in this TC-NER pathway’ he adds. While linked to aging, recent insights show that this repair pathway also protects against genome instability. Furthermore, this pathway plays an important role in clearing DNA damage induced by chemotherapeutics. It thereby helps to make sure our bodies don’t experience too much side effects of chemotherapy, like neurotoxicity.

Riding the DNA train

So, how does this latter work? In a cell there are many processes that use DNA as a template. It is a bit like having multiple trains driving towards each other or driving in the same direction at different speeds: eventually they can collide. And that can happen with the replication machinery and the transcription machinery in dividing cells. Usually this is well coordinated, so that a piece of DNA is never both replicated and transcribed at the same time. In comes the new study of Marteijn’s group. Without ELOF1, these conflicts start appearing upon DNA damage more often and have a nasty effect: an accumulation of mutations and genome instability, both risk factors for developing cancer.

Credit: Esther Morren, Erasmus MC

According to Marteijn’s findings, ELOF1 has three important functions which prevent this from happening. ´Firstly, ELOF1 is a so-called transcription elongation factor binding to RNA pol II´, Marteijn explains. ‘While RNA polymerase II is the major protein that does the hard work during transcription, it needs auxiliary factors like ELOF1 to make the process efficient. Secondly, ELOF1 is a crucial factor in TC-NER - it is indispensable the actual repair process. Thirdly, and perhaps the thing that surprised us the most, is the role of ELOF1 in protecting cells against transcription replication conflicts. So, how does this latter work? In a cell there are many processes that use DNA as a template. It is a bit like having multiple trains driving towards each other or driving in the same direction at different speeds: eventually they can collide. And that can happen with the replication machinery and the transcription machinery in dividing cells. Usually this is well coordinated, so that a piece of DNA is never both replicated and transcribed at the same time. In comes the new study of Marteijn’s group. Without ELOF1, these conflicts start appearing upon DNA damage more often and have a nasty effect: an accumulation of mutations and genome instability, both risk factors for developing cancer. It makes ELOF1 a multifunctional protein which plays a key role in genome integrity at multiple levels.’

All four TC-NER factors are important. Yet, there is a reason why ELOF1 was found only now. Historically, in the DNA repair field, important proteins are identified by analysing genetic material of patients that show DNA repair defects. It is how CSA and CSB pathways were identified in the 90’s, using cells originating from TC-NER deficient Cockayne syndrome patients. Then in 2012, Jurgen Marteijn’s lab identified UVSSA being defective in patients with UV sensitivity syndrome. But ELOF1 links to an essential gene – without it, life is not possible - and that most likely explains that there were not any patients identified with mutations in this gene. The journey that led to its discovery started with an Oncode collaboration with Rene Bernards’ lab, performing CRISPR/Cas9 whole genome screens. ‘This collaboration and the technology breakthrough were the basis of this discovery and made the difference. In the traditional way with patient groups, most likely we would have never found this gene’ says Marteijn. ‘Although this is basic research, it gives insight into how this important repair machinery works and protects against genome instability. This helps us to better understand the origins of cancer’ he concludes.

Other News

Oncode PEP4
(Future) researchers and patients join forces to make true impact
For the second year in a row, Oncode’s Patient Engagement Programme had the opportunity to contribute to the bachelor course ‘Eye for Impact’ for biomedical sciences students at University Medical Center Utrecht (UMCU). A unique example of how to give substance to patient engagement in basic research. Oncode researchers and patient representatives participated in a series of lectures and interactive sessions, where the students experienced first-hand how patients and researchers can partner up.
PeterThijssen
Jos Jonkers Daniel Zingg website
Unravelling genetic mechanism behind tumor formation can improve targeted treatment
New research by the group of Jos Jonkers explains variation in treatment response to FGFR2 inhibitors and provides a way to improve targeted therapy for cancer patients. Their work highlights the importance of analyzing the functional consequences of genetic variants found in tumors.
PeterThijssen
2
Chemotherapy speeds up DNA-level aging
Chemotherapy is an important part of treatment for children with cancer, contributing to the recovery of more and more children. Childhood cancer survivors do sometimes experience late effects from their treatment, including a higher risk of developing a second cancer. That risk is very small, but about five to six times greater than in the ‘normal’ population. In new research, published in Cancer Discovery, the team of Oncode Investigator Ruben Van Boxtel (Princess Máxima Center) shows that accelerated DNA aging turns out to be the main cause of the harmful effect of chemotherapy treatment.
PeterThijssen