Biology subjects

Marteijn, J.

Publications and source records attributed to Marteijn, J..

5 recordsLinked to original sources

bioRxiv2025

Dual Modes of Gene Regulation by CDK12

The process of transcription is driven forward by the activity of kinases including CDK7, CDK9 and CDK12. Accordingly, acute inhibition of any of these kinases results in profound downregulation of gene expression. Here, we discover that loss or inhibition of CDK12 also significantly upregulates a set of coding and non-coding loci, whose activation could contribute to the anti-proliferative effects of CDK12 inhibitors. Mechanistically, CDK12 inhibition impairs transcription elongation, leading to increased RNA polymerase II termination or arrest in long genes. However, short genes such as MYC and enhancer RNAs are highly transcribed in the absence of CDK12 activity. Indeed, in HER2+ breast cancer, a malignancy where CDK12 is co-amplified with HER2 and its expression correlates with disease status, CDK12 inhibition markedly elevates MYC expression to induce lethality. The dual effects of CDK12 inhibition elucidated herein clarify its role in transcriptional control and have significant translational implications.

cancer biology↗

bioRxiv2025

RNA polymerase II processing facilitates DNA repair and prevents DNA damage-induced neuronal and developmental failure

Hereditary transcription-coupled nucleotide excision repair (TC-NER) defects cause severe developmental and neurodegenerative features, as observed in Cockayne syndrome (CS), or mild cutaneous UV sensitivity, as observed in UV-sensitive syndrome. The mechanisms underlying the strikingly different clinical features of these syndromes are not fully understood. Using C. elegans, we demonstrate that TC-NER deficiency leads to DNA damage-induced motoneuronal and developmental failure, primarily caused by the lack of lesion removal due to persistent lesion-stalling of RNA polymerase II. If, in the absence of TC-NER, lesion-stalled RNA polymerase II is processed and removed, global genome NER acts as backup pathway to repair transcription-blocking lesions and prevents DNA damage-induced developmental failure. Our results furthermore show that processing of lesion-stalled RNA Polymerase II facilitates TC-NER and involves the activity of multiple E3 ubiquitin ligases. These findings reveal that persistently stalled RNA polymerase II, rather than TC-NER deficiency, is the major driver of severe disease features associated with TC-NER defects.

molecular biology↗

bioRxiv2023

Prolonged stalling of RNA Polymerase II at DNA damage explains phenotypical differences between Cockayne and UV-sensitive syndromes

Faithful transcription of eukaryotic genes by RNA polymerase II (Pol II) is essential for proper cell function. Nevertheless, the integrity of the DNA template of Pol II is continuously challenged by different sources of DNA damage, such as UV-light, that impede transcription. When unresolved, these transcription-blocking lesions (TBLs) can cause cellular dysfunction, senescence and apoptosis, eventually resulting in DNA damage-induced aging. Cells counteract these deleterious effects by Transcription-Coupled Nucleotide Excision Repair (TC-NER), which specifically removes TBLs, thereby safeguarding transcription. TC-NER initiation relies on the concerted actions of the CSB, CSA and UVSSA proteins, and loss of either of these factors results in a complete TC-NER deficiency. Although their TC-NER defect is similar, UVSSA loss results in UV-Sensitive Syndrome (UVSS), with only mild phenotypes like freckling and photosensitivity, while loss of CSA or CSB activity results in the severe Cockayne Syndrome (CS), characterized by premature aging, progressive neurodegeneration and mental retardation. Thus far the underlying mechanism for these striking differences in phenotypes remains unclear. Using live-cell imaging approaches, here we show that in TC-NER proficient cells lesion-stalled Pol II is swiftly resolved by repair of the TBL. However, in CSA and CSB knockout (KO) cells, elongating Pol II remains chromatin-bound. This lesion-stalled Pol II will obstruct other DNA transacting processes and will also shield the damage from repair by alternative pathways. In contrast, in UVSSA KO cells, Pol II is removed from the TBL by VCP-mediated proteasomal degradation, thereby, allowing alternative repair mechanisms to remove the TBL.

cell biology↗

bioRxiv2021

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

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 new 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 by two distinct mechanisms.

cell biology↗

bioRxiv2020

SMARCAD1 Mediated Active Replication Fork Stability Maintains Genome Integrity

Stalled fork protection pathway mediated by BRCA1/2 proteins is critical for replication fork stability that has implications in tumorigenesis. However, it is unclear if additional mechanisms are required to maintain replication fork stability. We describe a novel mechanism by which the chromatin remodeler SMARCAD1 stabilizes active replication forks that is essential for resistance towards replication poisons. We find that loss of SMARCAD1 results in toxic enrichment of 53BP1 at replication forks which mediates untimely dissociation of PCNA via the PCNA-unloader, ATAD5. Faster dissociation of PCNA causes frequent fork stalling, inefficient fork restart and accumulation of single-stranded DNA resulting in genome instability. Although, loss of 53BP1 in SMARCAD1 mutants restore PCNA levels, fork restart efficiency, genome stability and tolerance to replication poisons; this requires BRCA1 mediated fork protection. Interestingly, fork protection challenged BRCA1-deficient naive- or PARPi-resistant tumors require SMARCAD1 mediated active fork stabilization to maintain unperturbed fork progression and cellular proliferation.

cell biology↗