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Identifier

000419780

Title

Delineating the role of XAB2 in mammalian physiology

Alternative Title

Διελεύκανση του ρόλου της ΧΑΒ2 στη φυσιολογία των θηλαστικών

Author

Μπατσιώτος, Νικόλαος Π.

Thesis advisor

Γαρίνης, Γιώργος

Reviewer

Αλεξανδράκη, Δέσποινα
Ταλιανίδης, Γιάννης

Abstract

To maintain genome stability, which is continuously challenged by a variety of environmental and endogenous agents, cells have evolved a battery of DNA damage signaling and repair machineries. Nucleotide excision repair (NER), is a highly conserved pathway which repairs a broad class of helix-distorting lesions. NER defects are associated with cancer and premature aging, yet the neurological, developmental and metabolic abnormalities observed in NER syndromes cannot be explained only by the repair deficiency, which implies that NER factors function also beyond repair. Indeed, it is currently known that NER factors are also involved in transcription, chromatin remodelling and possibly pre-mRNA splicing. The possibility of a functional interplay between DNA damage repair/response and pre-mRNA splicing has recently emerged. Pre-mRNA splicing factors have been shown to either regulate, at the posttranscriptional level, the proper expression of DNA Damage Response (DDR) genes or be directly recruited at the site of damage. A protein linking pre-mRNA splicing with DNA repair is XPA Binding protein 2 (XAB2), which has been involved in NER, transcription and pre-mRNA splicing, its exact function, however, remains elusive. In order to investigate the functional contribution of XAB2 in hepatic physiology, biotin-tagged XAB2 mice were generated to allow the in vivo identification of the protein’s interactors. Here, we show that XAB2 is a partner of the core spliceosome, through its interaction with the PRP19 complex. Ablation of XAB2 results in defective splicing as shown by extensive intron retention, suggesting that XAB2 is indispensable for proper pre-mRNA processing. Moreover, we show that XAB2 binds pre-mRNAs and that this binding is lost in the presence of DNA damage leading to accumulation of unspliced pre-mRNA.

Language

English

Subject

Alternative splicing

DNA damage

DNA βλάβες

Εναλλακτικό μάτισμα

Issue date

2018-11-23

Collection

School/Department--School of Sciences and Engineering--Department of Biology--Post-graduate theses

Type of Work--Post-graduate theses