This thesis aims to gain a better understanding of NER, to elucidate new molecular mechanisms and proteins that orchestrate how DNA repair is carried out on genomic DNA that is tightly packed in... Show moreThis thesis aims to gain a better understanding of NER, to elucidate new molecular mechanisms and proteins that orchestrate how DNA repair is carried out on genomic DNA that is tightly packed in chromatin inside the living cell. It is important to obtain a better clinical picture of how inherited defects in DNA repair genes shapes phenotypes in patients with DNA repair-deficiency disorders. Show less
Jia, N.; Guo, C.W.; Nakazawa, Y.; Heuvel, D. van den; Luijsterburg, M.S.; Ogi, T. 2021
Transcription-blocking DNA lesions (TBLs) in genomic DNA are triggered by a wide variety of DNA-damaging agents. Such lesions cause stalling of elongating RNA polymerase II (RNA Pol II) enzymes and... Show moreTranscription-blocking DNA lesions (TBLs) in genomic DNA are triggered by a wide variety of DNA-damaging agents. Such lesions cause stalling of elongating RNA polymerase II (RNA Pol II) enzymes and fully block transcription when unresolved. The toxic impact of DNA damage on transcription progression is commonly referred to as transcription stress. In response to RNA Pol II stalling, cells activate and employ transcriptioncoupled repair (TCR) machineries to repair cytotoxic TBLs and resume transcription. Increasing evidence indicates that the modification and processing of stalled RNA Pol II is an integral component of the cellular response to and the repair of TBLs. If TCR pathways fail, the prolonged stalling of RNA Pol II will impede global replication and transcription as well as block the access of other DNA repair pathways that may act upon the TBL. Consequently, such prolonged stalling will trigger profound genome instability and devastating clinical features. In this review, we will discuss the mechanisms by which various types of TBLs are repaired by distinct TCR pathways and how RNA Pol II processing is regulated during these processes. We will also discuss the clinical consequences of transcription stress and genotype-phenotype correlations of related TCR-deficiency disorders. Show less
The work presented in this thesis has focused on the role of Mitogen Activated Protein Kinases (MAPKs) and their major downstream targets, the AP-1 transcription factors, in particular the AP-1... Show moreThe work presented in this thesis has focused on the role of Mitogen Activated Protein Kinases (MAPKs) and their major downstream targets, the AP-1 transcription factors, in particular the AP-1 components ATF3, Fra1, c-Jun, ATF-2 and c-Fos. Chapter II provides information on the signaling pathways involved in the activation of ATF-2 and ATF3 in the response of primary human fibroblasts to ionizing radiation. In chapter III c-Jun and ATF3, the MAPK JNK and the MAPK-phosphatase MKP-1 are identified as important sensors of UV-induced-DNA damage in transcribed genes. Chapter IV shows that ATF3 acts as an antiapoptotic JNK target in T98G glioblastoma cells, whereas Fra1 seems to act as a proapoptotic effector of both JNK and ERK. In addition, it is shown that ATF3 and Fra1 have opposite effects on cisplatin-induced S phase arrest. Chapter V shows that Fra1 also can exhibit a pro-apoptotic function in UV-irradiated fibroblasts. Furthermore, this chapter reports an as yet unknown function of JNK: repression of the transactivating activity of c-Jun/Fos(- like) dimers, mediated via hyper-phosphorylation of the c-Jun transactivation domain. The data further emphasizes that c-Jun/Fos(-like) and c-Jun/ATF dimers and their respective target genes can exhibit opposite functions in DNA damage responses. Show less
