# DCLRE1C

## Overview
The DCLRE1C gene encodes the Artemis protein, a crucial component of the DNA repair machinery, specifically involved in the non-homologous end joining (NHEJ) pathway and V(D)J recombination. Artemis is categorized as a structure-specific endonuclease and is a member of the metallo-β-lactamase (MBL) superfamily, characterized by its β-CASP domain. This protein plays a pivotal role in the immune system by facilitating the development of diverse immunoglobulin and T-cell receptor genes, essential for adaptive immunity. The Artemis protein is activated through phosphorylation by the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which enhances its ability to process DNA hairpins and overhangs, critical steps in DNA repair and recombination (Pannicke2010The; Felgentreff2015Functional). Mutations in the DCLRE1C gene can lead to severe combined immunodeficiency (SCID) and other immunodeficiency disorders, underscoring its clinical significance (Volk2015DCLRE1C(ARTEMIS) page 0 of 6).

## Structure
The DCLRE1C gene encodes the Artemis protein, which is a structure-specific endonuclease involved in DNA repair processes such as V(D)J recombination and non-homologous end joining (NHEJ). Artemis is a member of the metallo-β-lactamase (MBL) superfamily and contains a β-CASP domain. The protein's structure includes a core catalytic domain spanning amino acids 3-361, which is similar to other nucleases in the SNM1 family, such as SNM1A and SNM1B/Apollo (Yosaatmadja2021Structurala; Yosaatmadja2021Structural).

The MBL domain of Artemis features an α/β-β/α sandwich fold, while the β-CASP domain contains a unique zinc-finger-like motif. This motif is characterized by a tetrahedral geometry coordinated by two cysteine and two histidine residues, which is crucial for DNA binding and stability (Yosaatmadja2021Structurala; Yosaatmadja2021Structural). The active site of Artemis can coordinate one or two metal ions, typically zinc, which are essential for its endonucleolytic activity (Yosaatmadja2021Structural).

Artemis is activated by phosphorylation through the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which enhances its endonuclease activity on DNA hairpins and overhangs (Pannicke2010The; Felgentreff2015Functional). The protein also has several splice variant isoforms, which may influence its function and localization (Felgentreff2015Functional).

## Function
The DCLRE1C gene encodes the ARTEMIS protein, which plays a critical role in DNA repair and the immune system's development. ARTEMIS is involved in the non-homologous end joining (NHEJ) pathway, a crucial mechanism for repairing DNA double-strand breaks (DSBs) (Volk2015DCLRE1C(ARTEMIS) page 0 of 6). This protein is essential for V(D)J recombination, a process that generates diverse immunoglobulin and T-cell receptor genes necessary for adaptive immunity (Volk2015DCLRE1C(ARTEMIS) page 0 of 6; Pannicke2010The page 0 of 5).

ARTEMIS functions as a nuclease with both endonucleolytic and exonucleolytic activities, which are vital for resolving DNA intermediates during V(D)J recombination (Pannicke2004Functional; Poinsignon2004The). It is particularly important for opening hairpin structures at coding ends, a step required before the coding ends can be joined by the NHEJ pathway (Ma2002Hairpin; Pannicke2004Functional). The ARTEMIS protein is activated by phosphorylation through the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), enabling it to perform its nuclease activities (Pannicke2010The; Ma2002Hairpin).

In healthy human cells, ARTEMIS ensures proper V(D)J recombination, facilitating the development and function of B and T cells, which are crucial for a functional immune system (Volk2015DCLRE1C(ARTEMIS) page 0 of 6; Felgentreff2015Functional page 0 of 5). Mutations in the DCLRE1C gene can lead to severe combined immunodeficiency (SCID) due to impaired V(D)J recombination, resulting in defective B and T cell development (Volk2015DCLRE1C(ARTEMIS) page 0 of 6).

## Clinical Significance
Mutations in the DCLRE1C gene, which encodes the Artemis protein, are associated with a range of immunodeficiency disorders, most notably severe combined immunodeficiency (SCID). SCID is characterized by a lack of functional T and B lymphocytes, leading to life-threatening infections and impaired immune responses. The most common form of SCID associated with DCLRE1C mutations is the T-B-NK+ phenotype, where T and B cells are absent, but natural killer (NK) cells are present (Slatter2020Update; Ghadimi2023Demographic).

Patients with Artemis deficiency often present with recurrent infections, growth failure, and increased sensitivity to ionizing radiation. The condition is particularly prevalent among Athabascan-speaking Native Americans due to a founder mutation (Felgentreff2015Functional). Hypomorphic mutations in DCLRE1C can result in milder forms of immunodeficiency, such as atypical SCID, Omenn syndrome, or common variable immunodeficiency (CVID), which allow for some residual immune function (Volk2015DCLRE1C(ARTEMIS) page 0 of 6; Mou2021Compound page 0 of 3).

Autoimmune disorders, such as juvenile idiopathic arthritis and celiac disease, have also been reported in patients with non-SCID presentations of DCLRE1C mutations (Ghadimi2023Demographic). The severity of the clinical phenotype is influenced by the specific type and location of the mutation, affecting the levels of recombination and DNA repair activity (Felgentreff2015Functional).

## Interactions
The DCLRE1C gene encodes the Artemis protein, which is involved in DNA repair processes, particularly V(D)J recombination and non-homologous end joining (NHEJ). Artemis interacts with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form a stable complex essential for its function. This complex is crucial for hairpin opening and overhang processing during DNA repair and recombination. Artemis alone exhibits 5' to 3' exonuclease activity, but when complexed with DNA-PKcs, it gains endonucleolytic activity, allowing it to cleave 5' and 3' overhangs and open hairpins (Ma2002Hairpin).

The interaction between Artemis and DNA-PKcs involves multiple contact points, including the C-terminal regulatory region of Artemis and the FAT domain of DNA-PKcs. Mutations in DNA-PKcs, such as L3062R, can disrupt these interactions, affecting Artemis activation and end-joining activity (Watanabe2022Structural). Artemis also interacts with the XRCC4 and DNA ligase IV complex, which is involved in the transition to the DNA-PKcs:XRCC4:DNA ligase IV complex at broken DNA ends (Watanabe2022Structural).

Artemis is also involved in autoinhibition through interactions between its catalytic and C-terminal domains. Mutations affecting these interactions can lead to reduced protein stability and function, contributing to immunodeficiency disorders (Niewolik2017Autoinhibition).


## References


[1. (Slatter2020Update) Mary A. Slatter and Andrew R. Gennery. Update on dna-double strand break repair defects in combined primary immunodeficiency. Current Allergy and Asthma Reports, July 2020. URL: http://dx.doi.org/10.1007/s11882-020-00955-z, doi:10.1007/s11882-020-00955-z. This article has 16 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s11882-020-00955-z)

2. (Yosaatmadja2021Structural) Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition. This article has 24 citations.

[3. (Volk2015DCLRE1C(ARTEMIS) page 1 of 6) Timo Volk, Ulrich Pannicke, Ismail Reisli, Alla Bulashevska, Julia Ritter, Andrea Björkman, Alejandro A. Schäffer, Manfred Fliegauf, Esra H. Sayar, Ulrich Salzer, Paul Fisch, Dietmar Pfeifer, Michela Di Virgilio, Hongzhi Cao, Fang Yang, Karin Zimmermann, Sevgi Keles, Zafer Caliskaner, S¸ükrü Güner, Detlev Schindler, Lennart Hammarström, Marta Rizzi, Michael Hummel, Qiang Pan-Hammarström, Klaus Schwarz, and Bodo Grimbacher. Dclre1c(artemis) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. Human Molecular Genetics, 24(25):7361–7372, October 2015. URL: http://dx.doi.org/10.1093/hmg/ddv437, doi:10.1093/hmg/ddv437. This article has 70 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddv437)

[4. (Ma2002Hairpin) Yunmei Ma, Ulrich Pannicke, Klaus Schwarz, and Michael R. Lieber. Hairpin opening and overhang processing by an artemis/dna-dependent protein kinase complex in nonhomologous end joining and v(d)j recombination. Cell, 108(6):781–794, March 2002. URL: http://dx.doi.org/10.1016/s0092-8674(02)00671-2, doi:10.1016/s0092-8674(02)00671-2. This article has 841 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/s0092-8674(02)00671-2)

[5. (Felgentreff2015Functional) Kerstin Felgentreff, Yu Nee Lee, Francesco Frugoni, Likun Du, Mirjam van der Burg, Silvia Giliani, Ilhan Tezcan, Ismail Reisli, Ester Mejstrikova, Jean-Pierre de Villartay, Barry P. Sleckman, John Manis, and Luigi D. Notarangelo. Functional analysis of naturally occurring dclre1c mutations and correlation with the clinical phenotype of artemis deficiency. Journal of Allergy and Clinical Immunology, 136(1):140-150.e7, July 2015. URL: http://dx.doi.org/10.1016/j.jaci.2015.03.005, doi:10.1016/j.jaci.2015.03.005. This article has 63 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.jaci.2015.03.005)

[6. (Niewolik2017Autoinhibition) Doris Niewolik, Ingrid Peter, Carmen Butscher, and Klaus Schwarz. Autoinhibition of the nuclease artemis is mediated by a physical interaction between its catalytic and c-terminal domains. Journal of Biological Chemistry, 292(8):3351–3365, February 2017. URL: http://dx.doi.org/10.1074/jbc.m116.770461, doi:10.1074/jbc.m116.770461. This article has 22 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m116.770461)

[7. (Poinsignon2004The) Catherine Poinsignon, Despina Moshous, Isabelle Callebaut, Régina de Chasseval, Isabelle Villey, and Jean-Pierre de Villartay. The metallo-β-lactamase/β-casp domain of artemis constitutes the catalytic core for v(d)j recombination. The Journal of Experimental Medicine, 199(3):315–321, January 2004. URL: http://dx.doi.org/10.1084/jem.20031142, doi:10.1084/jem.20031142. This article has 70 citations.](https://doi.org/10.1084/jem.20031142)

[8. (Ghadimi2023Demographic) Soodeh Ghadimi, Mahnaz Jamee, Hassan Abolhassani, Nima Parvaneh, Nima Rezaei, Samaneh Delavari, Mahnaz Sadeghi-Shabestari, Sedigheh Rafiei Tabatabaei, Alireza Fahimzad, Shahnaz Armin, Zahra Chavoshzadeh, and Samin Sharafian. Demographic, clinical, immunological, and molecular features of iranian national cohort of patients with defect in dclre1c gene. Allergy, Asthma & Clinical Immunology, February 2023. URL: http://dx.doi.org/10.1186/s13223-023-00768-5, doi:10.1186/s13223-023-00768-5. This article has 6 citations.](https://doi.org/10.1186/s13223-023-00768-5)

[9. (Pannicke2004Functional) Ulrich Pannicke, Yunmei Ma, Karl-Peter Hopfner, Doris Niewolik, Michael R Lieber, and Klaus Schwarz. Functional and biochemical dissection of the structure-specific nuclease artemis. The EMBO Journal, 23(9):1987–1997, April 2004. URL: http://dx.doi.org/10.1038/sj.emboj.7600206, doi:10.1038/sj.emboj.7600206. This article has 109 citations.](https://doi.org/10.1038/sj.emboj.7600206)

[10. (Pannicke2010The) Ulrich Pannicke, Manfred Hönig, Ilka Schulze, Jan Rohr, Gitta A. Heinz, Sylvia Braun, Ingrid Janz, Eva-Maria Rump, Markus G. Seidel, Susanne Matthes-Martin, Jan Soerensen, Johann Greil, Daniel K. Stachel, Bernd H. Belohradsky, Michael H. Albert, Ansgar Schulz, Stephan Ehl, Wilhelm Friedrich, and Klaus Schwarz. The most frequentdclre1c(artemis) mutations are based on homologous recombination events. Human Mutation, 31(2):197–207, February 2010. URL: http://dx.doi.org/10.1002/humu.21168, doi:10.1002/humu.21168. This article has 45 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/humu.21168)

[11. (Yosaatmadja2021Structurala) Yuliana Yosaatmadja, Hannah T Baddock, Joseph A Newman, Marcin Bielinski, Angeline E Gavard, Shubhashish M M Mukhopadhyay, Adam A Dannerfjord, Christopher J Schofield, Peter J McHugh, and Opher Gileadi. Structural and mechanistic insights into the artemis endonuclease and strategies for its inhibition. Nucleic Acids Research, 49(16):9310–9326, August 2021. URL: http://dx.doi.org/10.1093/nar/gkab693, doi:10.1093/nar/gkab693. This article has 20 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gkab693)

[12. (Watanabe2022Structural) Go Watanabe, Michael R Lieber, and Dewight R Williams. Structural analysis of the basal state of the artemis:dna-pkcs complex. Nucleic Acids Research, 50(13):7697–7720, July 2022. URL: http://dx.doi.org/10.1093/nar/gkac564, doi:10.1093/nar/gkac564. This article has 15 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gkac564)