Xiong et al. Biomarker Research (2021) 9:16 https://doi.org/10.1186/s40364-021-00269-w REVIEW Open Access Diversity roles of CHD1L in normal cell function and tumorigenesis Xifeng Xiong1† , Xudong Lai2†, Aiguo Li1*, Zhihe Liu1* and Ningfang Ma3,4* Abstract Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a multifunctional protein participated in diverse cellular processes, including chromosome remodeling, cell differentiation and development. CHD1L is a regulator of chromosomal integrity maintenance, DNA repair and transcriptional regulation through its bindings to DNA. By regulating kinds of complex networks, CHD1L has been identified as a potent anti-apoptotic and pro- proliferative factor. CHD1L is also an oncoprotein since its overexpression leads to dysregulation of related downstream targets in various cancers. The latest advances in the functional molecular basis of CHD1L in normal cells will be described in this review. As the same time, we will describe the current understanding of CHD1L in terms of structure, characteristics, function and the molecular mechanisms underlying CHD1L in tumorigenesis. We inference that the role of CHD1L which involve in multiple cellular processes and oncogenesis is well worth further studying in basic biology and clinical relevance. Keywords: CHD1L, ALC1, SNF2, Chromatin remodeling, Tumorigenesis Introduction of nuclear activities, such as transcriptional inhibition or The CHD1L gene (Chromodomain helicase/ATPase activation, DNA recombination and repair [8, 9]. Like DNA binding protein 1-like gene), also called the ALC1 most SNF-like proteins, CHD1L is a regulator of gene (amplified in liver cancer 1), locates on chromo- chromosome integrity, transcriptional regulation and some 1q21 region of human hepatoma cells and is DNA repair through its bindings to DNA. The func- cloned by Guan using the comparative genomic tional diversity of CHD1L has always been related to the hybridization (CGH) technique [1–3]. Because CHD1L characteristics of helicases or chromatin remodeling en- has a consistent helicase sequence motif found in heli- zymes that interact with PAR and catalyze the sliding of case superfamily 2 proteins [1], it is classified as a su- nucleosomes stimulated by PAR polymerase 1 (PARP1) crose non-fermentation 2 like (SNF2-like) subfamily of [10, 11]. the SNF2 family [4–6]. Most SNF2-like proteins can CHD1L plays an important role as a transcription and utilize the energy, which is released from their DNA- translation activator of its target genes [1, 6, 12–19]. dependent ATPase activity, to stabilize or interfere with CHD1L can promote cell proliferation, enhance cell mi- protein-DNA interactions [7] and participate in a variety gration and inhibit apoptosis by regulating various com- plex networks [6, 12, 13]. For example, CHD1L is a well- known activator of ARHGEF9, TCTP, SPOCK1 and * Correspondence: [email protected]; [email protected]; – [email protected] NTKL [14 17] and can also lead to deregulation of p53, †Xifeng Xiong and Xudong Lai contributed equally to this work. TCTP and Nur77 [1, 15, 18]. Importantly, CHD1L 1 Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, shows carcinogenicity in the process of malignant trans- Jinan University, Guangzhou 510220, China 3Affiliated Cancer Hospital and Institute of Guangzhou Medical University, formation. CHD1L overexpression in cancer cells is Guangzhou 510095, China Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xiong et al. Biomarker Research (2021) 9:16 Page 2 of 18 considered as a biomarker of short tumor-free survival Characteristics and experssion pattern time and poor prognosis [12, 20–28]. CHD1L is a highly conserved gene among species in na- We will provide an overview of current understanding ture (https://www.ncbi.nlm.nih.gov/homologene/?term= about CHD1L on structure, characteristics, function and 11590). Human CHD1L is more than 87, 73, and 66% the molecular mechanisms underlying CHD1L in cancer similar to mammals, the less-evolved vertebrate chicken development in this review. As the same time, we will and zebrafish, respectively (Table 1). As conserved gene describe the latest development of CHD1L functions in in eukaryota (HomoloGene ID: 11590), CHD1L is in- normal cells. Finally, we will conclude that CHD1L is an volved in molecular function, cellular component, bio- attractively clinical target in the future molecular therapy logical process (Fig. 2a, Table 2)(http://www. of cancer. informatics.jax.org/homology/GOGraph/115 90#Annotations). Since CHD1L is expressed in many species including invertebrates, it appears that CHD1L Molecular and structural features of CHD1L exists in the common ancestor of vertebrates. In human, SNF2 superfamily CHD1L can be found in various tissues and exhibit dif- CHD1L protein belongs to the SNF2 superfamily pro- ferent expression patterns in space and time [22] (Fig. teins, which was identified by Ma [1]. The SNF2 super- 2b). For example, in the male reproductive system family proteins include ATP-dependent chromatin (testis), CHD1L is less expressed in mature cells than remodeling enzymes and play key roles in the progenitor cells [32, 33]. organization of genomic DNA in the natural chromatin state [7, 29]. The SNF2 superfamily proteins are further Biological function divided into ISWI (simulated switches), INO80 (inositol), Studies have described five spliced variants of the CHD (chromosomal domain helicase DNA binding) and CHD1L protein, and even found six spliced transcribed SWI/SNF (mating switch/non-sucrose fermentation) variants of the CHD1L gene [30]. Interestingly, CHD1L families [29]. In the mammalian, the ISWI family com- is a conserved protein with four conserved protein do- prises SNF2H and SNF2L. The SWI/SNF family proteins mains, namely SNF2_N domain, HELICc, SelS and contain brahma (BRM) and brahma-related gene 1 Macro domain (Fig. 1a). (BRG1). Based on the existence or nonexistence of add- SNF2_N domain is an important part of many proteins itional domains, the CHD family contains three subfam- that involved in a variety of cell biological processes in- ilies: Chd1-Chd2, Chd3-Chd4, and Chd5-Chd9 [29]. The cluding DNA repair, chromatin unwinding, DNA recom- CHD family has the characteristics of two signature se- bination, and transcription regulation, but also is quence motifs. One is the conserved SNF2_N domain at composed of some proteins with little functional infor- the N-terminal tandem chromodomain, and the other is mation [9, 34]. the SNF2-like ATPase domain at the center, also known HELICc is a component of multiple helicases and as the helicase superfamily c-terminal domain (HELICc) helicase-related proteins and DEAD-, DEXDc-, DEAH- [9]. The SNF2_N domains (containing 280 amino acids box associated proteins [35, 36], hepatitis C virus NS3, (aa)) of CHD1L and CHD1 have 45% identity, while ski2p and yeast initiation factor 4A [37]. The HELICc is their HELICc domains (containing 107 amino acids) not an autonomous folding unit, but is an essential part have 59% identity [1]. of the helicases that utilize the energy from nucleoside CHD1L is mapped to chromosome 1q21 [30]. The triphosphate hydrolysis to provide fuel for their trans- full-length messenger RNA of CHD1L (NM_004284.6) location along DNA and unwinding double-stranded contains 3036 base pairs with a presumptive open read- DNA in the process [36, 38]. The HELICc also contains ing frame encoding an 897 aa protein [1]. As shown in DEAD-like helicase superfamily (ATP-binding) region Fig. 1a, CHD1L mainly contains four domains: a con- which participates in ATP-dependent DNA or RNA served SNF2_N domains, a helicase superfamily domains unwinding. (HELICc), selenoprotein S (SelS) and a Macro domains SelS family contains several mammalian SelS se- [1]. The upstream of CHD1L gene is flavin containing quences. SelS is a disordered protein which has a seleno monooxygenase 5 (FMO5) gene, while the downstream sulfide bond (between Cys-174 and Sec-188) and a redox of which have a long intergenic non-coding RNA 624 potential (− 234 mV) [31]. SelS is an efficient reductase (LINC00624) and a prostaglandin reductase pseudo gene that can catalyze the reduction of hydrogen peroxide (LOC100130018) [30]. In addition, human CHD1L has a [39]. SelS also has the ability to resist hydrogen peroxide Selenoprotein S (SelS) region (579–695 aa), which is a inactivation and may have an evolutionary advantage plasma membrane protein that exists in many cell types compared to cysteine-containing peroxidases [40]. and tissues [31]. Schematic representation of human Macro domain is a high-affinity ADP-ribose binding CHD1L protein is shown in Fig. 1a. module, which exists in various proteins in the form of Xiong et al. Biomarker Research (2021) 9:16 Page 3 of 18 Fig. 1 (See legend on next page.) Xiong et al. Biomarker Research (2021) 9:16 Page 4 of 18 (See figure on previous page.) Fig. 1 Structural representation, transcriptional effects and regulatory pathways of CDH1L.