自噬 - 动物
中文名称
通路描述
自噬（或称巨自噬）是一种涉及蛋白质降解、细胞器周转以及细胞质成分非选择性降解的细胞代谢途径，在真核生物中进化保守，并受到精细调节。该过程始于自噬体的产生，这是一种具有双层膜的内细胞结构，起源于网状结构， engulf cytoplasmic contents 并最终与溶酶体融合以降解货物。自噬受细胞内外应激和信号（如饥饿、生长因子剥夺和内质网应激）的调节。自噬的基线水平对于细胞稳态至关重要，并维持对必需细胞成分的质控。
英文描述
Strand-asynchronous mitochondrial DNA replication The human mitochondrial genome is a circular double-stranded DNA of 16569 bp that encodes 2 rRNAs, 22 tRNAs, and 13 proteins. Based on density in a denaturing cesium chloride gradient, a heavy (H) strand and a light (L) strand are distinguishable. Two basic mechanisms of mitochondrial DNA replication have been proposed: (1) strand-asynchronous DNA replication (also called strand-displacement DNA replication), in which initiation of H strand synthesis significantly precedes initiation of L strand synthesis and each initiation is primed at a specific origin, and (2) strand-synchronous DNA replication, also called strand-coupled DNA replication, in which initiations of H strand synthesis and L strand synthesis occur concurrently and are primed by short RNA primers distributed through the genome (Yang et al. 2002, reviewed in Falkenberg 2018, Yasukawa and Kang 2018, Shokolenko and Alexeyev 2022, Falkenberg et al. 2024). Both types of synthesis may occur in mitochondria and the choice of synthesis type may depend on the abundance of the DNA helicase TWINKLE (TWNK, PEO1) and RNA transcripts (Cluett et al. 2018). The strand-asynchronous model has existed longer and has been more completely characterized (Uhler and Falkenberg 2021, Kosar et al. 2021). There is also some question of the evidence supporting the existence of RNA primers throughout the genome (Brown et al. 2005).
In the strand-asynchronous mechanism, the H strand is polymerized first from an origin of replication (OriH) located near the L strand promoter (LSP), which initiates transcription of the L strand as a template and a RNA corresponding to the sequence of the H strand as a product (Kang et al. 1997, Agaronyan et al. 2015, reviewed in Kasiviswanathan et al. 2012). The transcription elongation factor TEFM acts as a switch between transcription of the entire L strand and synthesis of a short primer for DNA replication (Agaronyan et al. 2015). The mitochondrial RNA polymerase POLRMT at LSP initiates synthesis of the H strand by polymerizing a short RNA of about 120 nucleotides that extends from the LSP to conserved sequence block 2 (CSB2) (Chang and Clayton 1985, Pham et al. 2006). The 3' end of the RNA is located in a G-quadruplex secondary structure that renders the 3' hydroxyl inaccessible for priming DNA synthesis and that creates a persistent R loop (Xu and Clayton 1996, Wanrooij et al. 2010, Wanrooij et al. 2012). RNASEH1 cleaves the RNA in the RNA-DNA duplex and creates accessible 3' hydroxyl groups (Posse et al. 2019, Misic et al. 2022).
The DNA helicase TWINKLE (TWNK, PEO1) and the mitochondrial DNA polymerase POLgamma, a complex comprising one subunit of POLG and two subunits of POLG2 (POLG:POLG2), bind the OriH region (Jemt et al. 2011, Jemt et al. 2015, Korhonen et al. 2004). TWNK binds as an open hexameric ring that closes around the DNA and hydrolyzes ATP to dissociate double-stranded DNA (Jemt et al. 2011, Jemt et al. 2015, Kaur et al. 2020, Kaur et al. 2021, reviewed in Peter and Falkenberg 2020) ahead of POLgamma, which uses the 3' hydroxyl groups of the RNA at OriH to begin polymerizing the nascent H strand (Johnson et al. 2000, Korhonen et al. 2004, Wanrooij et al. 2008, Plaza-G A et al. 2023). As polymerization proceeds, the parental H strand is displaced and bound by single strand binding protein 1 (SSBP1) (Miralles Fusté et al. 2014, Kaur et al. 2018, Plaza-G A et al. 2023). There is also evidence of long RNAs binding the displaced H strand (the "bootlace" model, Reyes et al. 2013).
Synthesis of the H strand continues until POLgamma passes the origin of L strand replication (OriL) about two thirds of the way around the 16569 bp genome. OriL becomes single-stranded and assumes a secondary loop structure that binds POLRMT, which synthesizes a short RNA that acts as a primer for DNA synthesis (Wanrooij et al. 2008, Fusté et al. 2010, Sarfallah et al. 2021). Significantly, OriL is required for mitochondrial maintenance in mice, evidence that the strand-asynchronous replication mechanism is essential (Wanrooij et al. 2012).
As POLgamma nears completion of the H and L strands, it migrates around the circular genome and reaches the 5' ends of the RNA primers. RNASEH1 cleaves all but two ribonucleotides from the primers in the nascent H and L strands (Ruhanen et al. 2011, Al-Behadili et al. 2018, reviewed in Uhler and Falkenberg 2015). Subsequent processing of the H and L strands differs slightly. A flap structure appears to be created by displacement at the 5' end of the H strand and the flap is removed by MGME1 (Uhler et al. 2016). A similar flap structure at the 5' end of the L strand is removed by another nuclease (Al-Behadili et al. 2018) that, based on in vitro evidence, may be EXOG (Wu et al. 2019, Karlowicz et al. 2022).
The remaining gaps in the H and L strands are ligated by the mitochondrial isoform of ligase III (LIG3-1) (Ruhanen et al. 2011). The resulting two double stranded mitochondrial genomes remain catenated by single strands which are resolved by topoisomerase 3A (TOP3A) (Nicholls et al. 2018).
In the strand-asynchronous mechanism, the H strand is polymerized first from an origin of replication (OriH) located near the L strand promoter (LSP), which initiates transcription of the L strand as a template and a RNA corresponding to the sequence of the H strand as a product (Kang et al. 1997, Agaronyan et al. 2015, reviewed in Kasiviswanathan et al. 2012). The transcription elongation factor TEFM acts as a switch between transcription of the entire L strand and synthesis of a short primer for DNA replication (Agaronyan et al. 2015). The mitochondrial RNA polymerase POLRMT at LSP initiates synthesis of the H strand by polymerizing a short RNA of about 120 nucleotides that extends from the LSP to conserved sequence block 2 (CSB2) (Chang and Clayton 1985, Pham et al. 2006). The 3' end of the RNA is located in a G-quadruplex secondary structure that renders the 3' hydroxyl inaccessible for priming DNA synthesis and that creates a persistent R loop (Xu and Clayton 1996, Wanrooij et al. 2010, Wanrooij et al. 2012). RNASEH1 cleaves the RNA in the RNA-DNA duplex and creates accessible 3' hydroxyl groups (Posse et al. 2019, Misic et al. 2022).
The DNA helicase TWINKLE (TWNK, PEO1) and the mitochondrial DNA polymerase POLgamma, a complex comprising one subunit of POLG and two subunits of POLG2 (POLG:POLG2), bind the OriH region (Jemt et al. 2011, Jemt et al. 2015, Korhonen et al. 2004). TWNK binds as an open hexameric ring that closes around the DNA and hydrolyzes ATP to dissociate double-stranded DNA (Jemt et al. 2011, Jemt et al. 2015, Kaur et al. 2020, Kaur et al. 2021, reviewed in Peter and Falkenberg 2020) ahead of POLgamma, which uses the 3' hydroxyl groups of the RNA at OriH to begin polymerizing the nascent H strand (Johnson et al. 2000, Korhonen et al. 2004, Wanrooij et al. 2008, Plaza-G A et al. 2023). As polymerization proceeds, the parental H strand is displaced and bound by single strand binding protein 1 (SSBP1) (Miralles Fusté et al. 2014, Kaur et al. 2018, Plaza-G A et al. 2023). There is also evidence of long RNAs binding the displaced H strand (the "bootlace" model, Reyes et al. 2013).
Synthesis of the H strand continues until POLgamma passes the origin of L strand replication (OriL) about two thirds of the way around the 16569 bp genome. OriL becomes single-stranded and assumes a secondary loop structure that binds POLRMT, which synthesizes a short RNA that acts as a primer for DNA synthesis (Wanrooij et al. 2008, Fusté et al. 2010, Sarfallah et al. 2021). Significantly, OriL is required for mitochondrial maintenance in mice, evidence that the strand-asynchronous replication mechanism is essential (Wanrooij et al. 2012).
As POLgamma nears completion of the H and L strands, it migrates around the circular genome and reaches the 5' ends of the RNA primers. RNASEH1 cleaves all but two ribonucleotides from the primers in the nascent H and L strands (Ruhanen et al. 2011, Al-Behadili et al. 2018, reviewed in Uhler and Falkenberg 2015). Subsequent processing of the H and L strands differs slightly. A flap structure appears to be created by displacement at the 5' end of the H strand and the flap is removed by MGME1 (Uhler et al. 2016). A similar flap structure at the 5' end of the L strand is removed by another nuclease (Al-Behadili et al. 2018) that, based on in vitro evidence, may be EXOG (Wu et al. 2019, Karlowicz et al. 2022).
The remaining gaps in the H and L strands are ligated by the mitochondrial isoform of ligase III (LIG3-1) (Ruhanen et al. 2011). The resulting two double stranded mitochondrial genomes remain catenated by single strands which are resolved by topoisomerase 3A (TOP3A) (Nicholls et al. 2018).
所含基因
9 个基因