# POLH

## Overview
The POLH gene encodes DNA polymerase eta (Pol η), a member of the Y-family of DNA polymerases, which is primarily involved in translesion synthesis (TLS), a DNA damage tolerance process. Pol η is characterized by its ability to bypass DNA lesions, such as those induced by ultraviolet (UV) light, with high fidelity, thereby preventing mutations that could lead to genomic instability (Bétous2008Role; Liu2006DNA). Structurally, Pol η comprises a catalytic N-terminal domain and a protein-interacting C-terminal domain, which includes motifs for interacting with proliferating cell nuclear antigen (PCNA) and ubiquitin, essential for its recruitment and function at replication forks (Saha2020DNA; Jung2022Contributing). Mutations in the POLH gene are linked to xeroderma pigmentosum variant (XP-V), a disorder marked by increased UV sensitivity and cancer risk due to impaired TLS (Masutani1999The; Kannouche2001Domain). Beyond its role in DNA repair, Pol η is implicated in processes such as homologous recombination repair and the alternative lengthening of telomeres, underscoring its multifaceted contributions to cellular homeostasis (Eckert2023Nontraditional; McIlwraith2005Human).

## Structure
DNA polymerase eta (Pol η), encoded by the POLH gene, is a Y-family polymerase consisting of 713 amino acids. The primary structure of Pol η includes a catalytic N-terminal domain and a protein-interacting C-terminal domain (Jung2022Contributing). The N-terminal catalytic domain features conserved domains typical of Y-family polymerases, such as the finger, thumb, palm, and little finger domains, which form a right-hand shape (Jung2022Contributing). This domain is responsible for bypassing various DNA lesions, including cyclobutane pyrimidine dimers (CPD) and 8-oxoguanine (Jung2022Contributing).

The C-terminal domain contains two proliferating cell nuclear antigen (PCNA) interacting peptide (PIP) domains, a Rev1 interacting region (RIR), a ubiquitin-binding zinc finger (UBZ) domain, and a nuclear localization signal (NLS) (Saha2020DNA; Jung2022Contributing). The UBZ domain is involved in interactions with ubiquitin, which may influence the protein's activity and interactions (Jung2022Contributing).

Pol η undergoes post-translational modifications such as ubiquitination and phosphorylation, which affect its function and interactions with other proteins (Jung2022Contributing). The protein's structure allows it to maintain the B-conformation of DNA even in the presence of bulky lesions, a unique feature among Y-family polymerases (Saha2020DNA).

## Function
DNA polymerase eta (POLH) plays a crucial role in maintaining genomic stability in healthy human cells by participating in DNA repair processes, particularly translesion synthesis (TLS) and homologous recombination repair (HRR). POLH is unique among eukaryotic polymerases for its ability to extend primers on D loop structures, which are intermediates in HRR, facilitating DNA synthesis from strand invasion intermediates (McIlwraith2005Human). This function is essential for restarting collapsed replication forks and maintaining genome integrity (McIlwraith2005Human).

POLH is also involved in bypassing DNA lesions that block replication fork progression, such as UV-induced cyclobutane pyrimidine dimers, by inserting nucleotides opposite damaged sites in an error-free manner (Bétous2008Role; Liu2006DNA). This process is facilitated by the monoubiquitination of PCNA, which increases POLH's affinity for the replication machinery, allowing it to temporarily replace other polymerases like POLD (McIlwraith2005Human).

In addition to its role in DNA repair, POLH is implicated in the alternative lengthening of telomeres (ALT) pathway, somatic hypermutation of immunoglobulin genes, and cell fate regulation, highlighting its diverse functions in cellular processes (Eckert2023Nontraditional). POLH's activity is primarily localized in the nucleus, where it interacts with proteins involved in DNA replication and repair, such as RAD51 and PCNA (Kannouche2001Domain).

## Clinical Significance
Mutations in the POLH gene, which encodes DNA polymerase η, are primarily associated with xeroderma pigmentosum variant (XP-V), a condition characterized by increased sensitivity to ultraviolet (UV) light and a heightened risk of skin cancer. XP-V patients exhibit normal nucleotide excision repair but have defects in translesion synthesis (TLS), a process crucial for bypassing UV-induced DNA damage. This defect leads to an inability to synthesize intact daughter DNA strands post-UV irradiation, resulting in a high mutation rate and increased cancer risk (Masutani1999The; Kannouche2001Domain).

The POLH gene mutations in XP-V patients include severe truncations, missense mutations, and C-terminal truncations. These mutations can impair the protein's nuclear localization and its ability to accumulate at replication foci, crucial for its function in TLS (Kannouche2001Domain; Broughton2002Molecular). Some mutations, particularly those affecting the C-terminal region, disrupt interactions with other cellular components, such as the proliferating cell nuclear antigen, which is essential for maximal activity (Broughton2002Molecular).

Additionally, variants of the POLH gene, such as the c.1783G>A p.M595V variant, have been associated with an increased risk of melanoma, particularly in populations with high UV exposure. This variant may affect POLH's TLS activity and mRNA stability, contributing to melanoma susceptibility (Di2009Variants).

## Interactions
DNA polymerase eta (POLH) interacts with several proteins and nucleic acids, playing a crucial role in translesion DNA synthesis (TLS). A key interaction is with proliferating cell nuclear antigen (PCNA), which is essential for POLH's recruitment to replication forks and its function in TLS. POLH contains PCNA-interacting protein (PIP) motifs, specifically PIP1 and PIP2, which facilitate its binding to PCNA. Mutations in these motifs impair POLH's ability to bind PCNA and perform TLS, highlighting their importance (Acharya2008Roles).

POLH also interacts with ubiquitin through its ubiquitin-binding zinc finger (UBZ) domain. This interaction is involved in the regulation of POLH's activity, although it is not essential for its binding to PCNA or its function in TLS (Acharya2008Roles). The UBZ domain, while not critical for PCNA binding, contributes to POLH's ability to confer UV resistance, suggesting a role in other cellular processes (Acharya2008Roles).

Additionally, POLH undergoes multisite SUMOylation, which regulates its interactions with DNA damage sites. This modification, facilitated by RAD18 and PIAS1, ensures that POLH's interactions with PCNA are dynamic, preventing excessive mutagenesis (Guérillon2020Multisite; Despras2016Rad18dependent).


## References


[1. (Masutani1999The) Chikahide Masutani, Rika Kusumoto, Ayumi Yamada, Naoshi Dohmae, Masayuki Yokoi, Mayumi Yuasa, Marito Araki, Shigenori Iwai, Koji Takio, and Fumio Hanaoka. The xpv (xeroderma pigmentosum variant) gene encodes human dna polymerase η. Nature, 399(6737):700–704, June 1999. URL: http://dx.doi.org/10.1038/21447, doi:10.1038/21447. This article has 1067 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/21447)

[2. (Di2009Variants) Julie Di Lucca, Mickael Guedj, Jean-Jacques Lacapère, Maria Concetta Fargnoli, Agnes Bourillon, Philippe Dieudé, Nicolas Dupin, Pierre Wolkenstein, Philippe Aegerter, Philippe Saiag, Vincent Descamps, Celeste Lebbe, Nicole Basset-Seguin, Ketty Peris, Bernard Grandchamp, and Nadem Soufir. Variants of the xeroderma pigmentosum variant gene (polh) are associated with melanoma risk. European Journal of Cancer, 45(18):3228–3236, December 2009. URL: http://dx.doi.org/10.1016/j.ejca.2009.04.034, doi:10.1016/j.ejca.2009.04.034. This article has 34 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.ejca.2009.04.034)

[3. (Liu2006DNA) Gang Liu and Xinbin Chen. Dna polymerase η, the product of the xeroderma pigmentosum variant gene and a target of p53, modulates the dna damage checkpoint and p53 activation. Molecular and Cellular Biology, 26(4):1398–1413, February 2006. URL: http://dx.doi.org/10.1128/mcb.26.4.1398-1413.2006, doi:10.1128/mcb.26.4.1398-1413.2006. This article has 88 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.26.4.1398-1413.2006)

[4. (Saha2020DNA) Priyanka Saha, Tanima Mandal, Anupam D. Talukdar, Deepak Kumar, Sanjay Kumar, Prem P. Tripathi, Qi‐En Wang, and Amit K. Srivastava. Dna polymerase eta: a potential pharmacological target for cancer therapy. Journal of Cellular Physiology, 236(6):4106–4120, November 2020. URL: http://dx.doi.org/10.1002/jcp.30155, doi:10.1002/jcp.30155. This article has 23 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/jcp.30155)

[5. (McIlwraith2005Human) Michael J. McIlwraith, Alexandra Vaisman, Yilun Liu, Ellen Fanning, Roger Woodgate, and Stephen C. West. Human dna polymerase η promotes dna synthesis from strand invasion intermediates of homologous recombination. Molecular Cell, 20(5):783–792, December 2005. URL: http://dx.doi.org/10.1016/j.molcel.2005.10.001, doi:10.1016/j.molcel.2005.10.001. This article has 248 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.molcel.2005.10.001)

[6. (Bétous2008Role) Rémy Bétous, Laurie Rey, Guliang Wang, Marie‐Jeanne Pillaire, Nadine Puget, Janick Selves, Denis S.F. Biard, Kazuo Shin‐ya, Karen M. Vasquez, Christophe Cazaux, and Jean‐Sébastien Hoffmann. Role of tls dna polymerases eta and kappa in processing naturally occurring structured dna in human cells. Molecular Carcinogenesis, 48(4):369–378, December 2008. URL: http://dx.doi.org/10.1002/mc.20509, doi:10.1002/mc.20509. This article has 104 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/mc.20509)

[7. (Broughton2002Molecular) Bernard C. Broughton, Agnes Cordonnier, Wim J. Kleijer, Nicolaas G. J. Jaspers, Heather Fawcett, Anja Raams, Victor H. Garritsen, Anne Stary, Marie-Françoise Avril, François Boudsocq, Chikahide Masutani, Fumio Hanaoka, Robert P. Fuchs, Alain Sarasin, and Alan R. Lehmann. Molecular analysis of mutations in dna polymerase η in xeroderma pigmentosum-variant patients. Proceedings of the National Academy of Sciences, 99(2):815–820, January 2002. URL: http://dx.doi.org/10.1073/pnas.022473899, doi:10.1073/pnas.022473899. This article has 136 citations.](https://doi.org/10.1073/pnas.022473899)

[8. (Jung2022Contributing) Hunmin Jung. Contributing factors for mutagenic dna lesion bypass by dna polymerase eta (polη). DNA, 2(4):205–220, September 2022. URL: http://dx.doi.org/10.3390/dna2040015, doi:10.3390/dna2040015. This article has 4 citations.](https://doi.org/10.3390/dna2040015)

[9. (Acharya2008Roles) Narottam Acharya, Jung-Hoon Yoon, Himabindu Gali, Ildiko Unk, Lajos Haracska, Robert E. Johnson, Jerard Hurwitz, Louise Prakash, and Satya Prakash. Roles of pcna-binding and ubiquitin-binding domains in human dna polymerase η in translesion dna synthesis. Proceedings of the National Academy of Sciences, 105(46):17724–17729, November 2008. URL: http://dx.doi.org/10.1073/pnas.0809844105, doi:10.1073/pnas.0809844105. This article has 94 citations.](https://doi.org/10.1073/pnas.0809844105)

[10. (Guérillon2020Multisite) Claire Guérillon, Stine Smedegaard, Ivo A. Hendriks, Michael L. Nielsen, and Niels Mailand. Multisite sumoylation restrains dna polymerase η interactions with dna damage sites. Journal of Biological Chemistry, 295(25):8350–8362, June 2020. URL: http://dx.doi.org/10.1074/jbc.ra120.013780, doi:10.1074/jbc.ra120.013780. This article has 17 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.ra120.013780)

[11. (Kannouche2001Domain) Patricia Kannouche, Bernard C. Broughton, Marcel Volker, Fumio Hanaoka, Leon H.F. Mullenders, and Alan R. Lehmann. Domain structure, localization, and function of dna polymerase η, defective in xeroderma pigmentosum variant cells. Genes & Development, 15(2):158–172, January 2001. URL: http://dx.doi.org/10.1101/gad.187501, doi:10.1101/gad.187501. This article has 230 citations.](https://doi.org/10.1101/gad.187501)

[12. (Eckert2023Nontraditional) Kristin A. Eckert. Nontraditional roles of dna polymerase eta support genome duplication and stability. Genes, 14(1):175, January 2023. URL: http://dx.doi.org/10.3390/genes14010175, doi:10.3390/genes14010175. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/genes14010175)

[13. (Despras2016Rad18dependent) Emmanuelle Despras, Méghane Sittewelle, Caroline Pouvelle, Noémie Delrieu, Agnès M Cordonnier, and Patricia L Kannouche. Rad18-dependent sumoylation of human specialized dna polymerase eta is required to prevent under-replicated dna. Nature Communications, November 2016. URL: http://dx.doi.org/10.1038/ncomms13326, doi:10.1038/ncomms13326. This article has 64 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/ncomms13326)