Year: 2012
Type: article
Abstract: NIKOLE TEMINA LOTTMethylation of histones has recently emerged as a key regulatory mechanism for a variety of cellular processes.Here I focus on the regulation of the histone H4 lysine 20 methyltransferase, Kmt5, and its role in genome stability.The recruitment of the checkpoint protein Crb2 to sites of DNA damage was known to be dependent upon the presence of H4K20 methylation, but the specific methylation state required was unknown.I show that the Tudor domain of Crb2 specifically recognizes and binds to H4K20me2 at sites of genome damage in order to maintain the G2/M cell cycle checkpoint.The Kmt5 methyltransferase however, does not localize to sites of damage to locally enrich the H4K20me2 signal required for this interaction.The Kmt5 methyltransferase is shown to interact specifically with Pdp1 and potentially other proteins as a means of regulating the activity of the methyltransferase.An unexpected connection between Kmt5 and mitochondria was identified, suggesting a novel role for the methyltransferase in addition to its previously known H4K20 methyltransferase responsibilities.These results suggest a complex network of interactions that regulate the activity of the Kmt5 methyltransferase. CHAPTER 1: INTRODUCTION 1.1: The chromatin problemThe genetic information that determines the diversity of life is encoded by the double helix of DNA (1).However, in a eukaryotic nucleus, this genetic material is not naked but is tightly wrapped in the protein-nucleic acid complex of chromatin (2,3).The building block of chromatin is the nucleosome, a repeating subunit of about two turns of DNA wrapped around an octameric structure of core histone proteins (4,5).The octamer core is built from two copies each of four histones, H2A, H2B, H3, and H4, organized with a pair of H2A-H2B dimers flanking either side of an H3-H4 tetramer (4).Together the core histones form a highly structured globular complex, with the exception of their N-terminal tail regions that are unstructured and are thought to protrude away from the core nucleosome (Figure 1.1) (4,6).A central function of chromatin is to package the long strands of DNA to a size that fits into a confined nuclear volume.For example, ~1.8 meters of DNA is compacted ~400,000 fold to fit within the ~1000 µm 3 nuclear volume of a typical human cell (7,8).Although chromatin packaging is a highly efficient means of storing DNA and is essential for transmitting the genetic material through successive generations, it creates a significant problem of accessibility because many processes that read the genetic code, such as transcription and DNA repair, are inhibited by the compact nature of the chromatin template (9,10).Although once viewed as a static structure, it is now appreciated that chromatin is highly dynamic and that structural variation is a common theme for regulating genome activity
Author: Nikole T. Lott
Institution: Case Western Reserve University
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2612594089