Based on the lecture material, describe how the association of DNMT1 with the following
proteins ensures that it willbe found on hemimethylated DNA.
UHRF1
PCNA
In humans, DNA cytosine methylation is an important process in conserved epigenetic
inheritance. This is necessary for the development of the embryo, regulation of the transcription
and stability of the genome. This DNA methylation determines the cellular phenotypes in higher
eukaryotes or in mammals so this process should be maintained during the DNA replication,
specifically during the S or synthesis phase of the cell cycle. So, the DNA (cytosine-5)-
methyltransferase 1 or DNMT 1 is an enzyme that transfer methyl groups, which consists of one
carbon atom and three hydrogen atoms) to specific CpG (cytosine-5) residues or fifth carbon of
cytosines in DNA. They are found in the replication forks during the S phase of the cell cycle.
The DNMT 1 are both recruited and interacts with Ubiquitin-like PHD and RING finger domain
1 (UHRF 1) and proliferating cell nuclear antigen (PCNA). UHRF 1 is a multidomain protein
that functions as an epigenetic control. This regulation is done by this protein by bridging DNA
methylation and chromatin modification. This protein also recognizes and binds selectively to
hemimethylated DNA at replication forks via its YDG domain targeting the DNMT 1
methyltransferase to ensure that the DNA methylation patterns is followed through the DNA
replication. It accumulates in nuclear loci during the mid to late S phase ensuring the recruitment
of DNMT1 on hemi-methylated DNA. This interaction of UHRF1 and DNMT1 involves a
functional SET and RING-associated (SRA) domains that also recognizes hemi-methylated CpG
residues on DNA and the three independent regions of DNMT1 This binding activity ensures the
maintenance of DNA methylation. While the proliferating cell nuclear antigen or PCNA
primarily functions in DNA binding. It is a cofactor of DNA polymerase delta and interacts with
DNMT1. It is also a regulator of eukaryotic DNA replication by increasing the polymerase the
capacity to handle during elongation of the leading strand. The PCNA also place an important
role in DNA damage and repair by being positioned at the replication fork to help in the DNA
repair and tolerance pathways during the DNA replication. Through the PCNA, it guarantees that
DNA methylation occurs and DNMT1 will be found on the hemimethylated DNA by increasing
the affinity of DNMT1 to the DNA.
References:
Hervouet, E., Peixoto, P., Delage-Mourroux, R. et al. (2018). Specific or not specific recruitment
of DNMTs for DNA methylation, an epigenetic dilemma. Clinical Epigenetics 10, 17.
https://doi.org/10.1186/s13148-018-0450-y
Nishiyama, A., Mulholland, C.B., Bultmann, S. et al. (2020). Two distinct modes of DNMT1
recruitment ensure stable maintenance DNA methylation. Nature Communications 11,
1222. https://doi.org/10.1038/s41467-020-15006-4
Medline Plus. (2020). DNA methyltransferase 1 gene. U.S. National Library of Medicine.
Retrieved May 30, 2021 from: https://medlineplus.gov/genetics/gene/dnmt1/
