DNA Damage-Induced RNAPII Degradation and Its Consequences in Gene Expression

Abstract

RPB1, the major and catalytic subunit of human RNA Polymerase II (RNAPII), is specifically degraded by the ubiquitin-proteasome system upon induction of DNA damage by different agents, such as ultraviolet (UV) light. The "last resort" model of RNAPII degradation states that a persistently stalled RNAPII is degraded at the site of the DNA lesion in order to facilitate access to Nucleotide Excision Repair (NER) factors, thereby promoting repair in template strands of active genes. Recent identification and mutation of the lysine residue involved in RPB1 ubiquitylation and degradation unveiled the relevance of RNAPII levels in the control of gene expression. Inhibition of RNAPII degradation after UV light exposure enhanced RNAPII loading onto chromatin, demonstrating that the mere concentration of RNAPII shapes the gene expression response. In this review, we discuss the role of RNAPII ubiquitylation in NER-dependent repair, recent advances in RPB1 degradation mechanisms and its consequences in gene expression under stress, both in normal and repair deficient cells.

Keywords: DNA damage; RNAPII degradation; UV light; gene expression; nucleotide excision repair.

Figure 1

Model of Transcription-Coupled recognition of DNA damage. Stalling of RNAPII induces the recruitment of CSB and the E3 ligase complex CRL4CSA, which stands as the major contributor to RPB1 K1268 ubiquitylation upon UV, although other E3 ligases might be involved (see references [8,28,29]). Once RPB1 is ubiquitylated, UVSSA is recruited and ubiquitylated in its K414 residue, which facilitates TFIIH binding to the stalled complex. In order to expose the lesion and hand it over to TFIIH, the stalled RNAPII must backtrack, at least, a few nucleotides. Recruitment of TFIIH is the point at which GG-NER and TC-NER converge in the same mechanism in charge of completing the repair process. For more information regarding the fate of the ubiquitylated RPB1, see Figure 2.

Figure 2

Possible RPB1 degradation pathways. RPB1 degradation upon DNA damage induction has been historically associated with a last resort, where RPB1 is degraded in cis to the DNA lesion, in order to facilitate access to TC-NER repair factors [8] (center). More recently, in trans degradation of promoter-proximal paused RPB1 has been proposed [30,31] (left) and VCP/p97 segregase independent degradation of RPB1 were also shown, opening the possibility of chromatin unbound RBP1 degradation [32] (right).